Pi4kiiibeta inhibitors

ABSTRACT

The invention relates to compounds of formula (1) which are inhibitors of kinase activity, pharmaceutical formulations containing the compounds and their uses in treating and preventing viral infections and disorders caused or exacerbated by the viral infection 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4a , R 4b , R 4c , R 5 , W, X, Y and Z are defined herein.

FIELD OF INVENTION

The invention relates to compounds which are inhibitors of kinaseactivity, pharmaceutical formulations containing the compounds and theiruses in treating and preventing viral infections and disorders caused orexacerbated by the viral infection.

BACKGROUND OF THE INVENTION

The genus Enterovirus of the family Picornaviridae of positive sensesingle stranded RNA viruses includes a number of human pathogens thatcan cause very serious illnesses. Examples include polio virus, coxsakieB virus (aseptic meningitis, myocarditis, pancreatitis and non-specificfebrile illness), enterovirus-A71 (aseptic meningitis, encephalitis andpoliomyelitis-like paralysis), enterovirus-D68 (acute flaccid myelitis)and parechovirus (myocarditis and encephalitis). Enteroviral infections(coxsackievirus A24 variant and enterovirus type 70) are responsible formost cases of acute hemorrhagic conjunctivitis (AHC) and there have beennumerous AHC epidemics and three pandemics since 1969 (Yin-Murphy etal., British Journal of Ophthalmology, 1986, 70, 869; Nilsson et al.,Journal of Virology, 2008 82, 3061). However, most people experiencingan enteroviral infection suffer much less serious illness. The commoncold is one of the most frequently occurring human illnesses and is mostoften associated with another species of enterovirus, the humanrhinovirus (HRV) which causes of 30-50% colds.

The optimal temperature for HRV replication is 33-35° C., favouringupper respiratory tract infection (URTI) and an illness that is mostoften mild and resolved without medical intervention. However, UTRI canhave complications and HRV was detected in the middle ear of ˜40% ofchildren under 7 years of age suffering from otitis media with effusion,including chronic cases (Papadopoulus et al., Paediatric Allergy andImmunology, 2006: 17: 514), in sputum in 26% of 291 patients sufferingfrom acute bronchitis (Park et al. Plos One, 2016, 11, e0165553), inmaxillary aspirates and brushings from 15 of 34 patients suffering fromacute sinusitis, (PitkAranta et al., Journal of Clinical Microbiology,1997, 35, 1791 and Clinical Infectious Diseases, 2001 33, 909) and in29% of patients undergoing functional endoscopic sinus surgery forchronic rhinosinusitis (Abshirini et al., Jundishapur Journal ofMicrobiology, 2015, 8, e20068).

The temperature of large and medium sized airways of the lung shouldalso permit HRV replication (McFadden E R Jr, et al., J. Appl. Physiol.,1985, 58, 564) and in certain patient groups infection can cause veryserious illness. In children under 5 years of age, rhinovirus infectionfrequently leads to hospitalisation (4.8 cases/1000 children: Miller etal., Journal of Infectious Diseases, 2007; 195, 773), a severity ofillness similar to that from respiratory syncytial virus (RSV) infection(McMillan et al., Pediatric Infectious Disease Journal, 1993, 12, 321)and often leads to bronchiolitis and pneumonia (Kellner et al., ActaPaediatrica Scandinavica, 1989, 78, 390; McMillan et al., PediatricInfectious Disease Journal, 1993, 12, 321; El-Sahly et al., Clinicalinfectious Diseases, 2000, 31, 96; Jartti and Korppi, Pediatric Allergyand Immunology, 2011, 22, 350). In a study by Asner et al. (Influenzaand Other espiratory Viruses, 2014, 8, 436) the majority of theHRV/enterovirus infected children had underlying immunosupression orcardiorespiratory co-morbidities and it is well established that theconsequences of HRV infection can be particularly serious for patientswith these conditions (Anzueto et al., Chest, 2003, 123, 1664; Rotbart,Antivir. Res. 2002, 53, 83). For example, 7 of 22 myelosuppressedtransplant recipients with a rhinovirus infection went on to developfatal pneumonia (Ghosh et al., Clinical infectious Diseases, 1999, 29,528).

Enterovirus infections are also commonly associated with eruptive skinrashes (hand foot and mouth disease, eczema coxsackium and otheratypical exanthems: Hubisch et al., Pediatric Infectious DiseaseJournal, 2014, 33, e92; Korman et al., Journal of the American Academyof Dermatology, 2017, 76, 538; Drago et al., Future Microbiology, 201712, 171).

HRV is the virus most commonly associated with exacerbations of asthma(approximately 25% exacerbations in adults and 50% in children,Nicholson et al., BMJ, 1993, 307, 982; Johnston et al., BMJ., 199, 310,1225) and chronic obstructive pulmonary disease (COPD: 20-26% Seemungalet al., Am. J. Respir. Crit. Care Med., 2001, 164, 1618; Papi et al.,Am. J. Respir. Crit. Care Med., 2006, 173, 1114), and in both casesexperimental rhinoviral challenge has been shown to exacerbate disease(Zambrano et al., J Allergy Clin Immunol., 2003, 111, 1008; Mallia etal., Am. J. Respir. Crit. Care Med., 2011, 183, 734). Rhinoviralinfections are also frequently associated with exacerbations ofbronchiectasis (16 to 25%: Kapur et al. Arch Dis Child 2014, 99, 749;Gao et al Chest 2015, 147, 1635) and cystic fibrosis (CF) (Etherington,J. Cystic Fibrosis 2014, 13, 49; Flight et al. Thorax, 2014, 69, 247).In COPD, CF and bronchectasis exacerbations are more severe whenassociated with viral infection (Papi et al. Am. J. Respir. Crit. CareMed., 2006, 173, 1114; Etherington, J. Cystic Fibrosis, 2014, 13, 49;Kapur et al., Arch Dis Child, 2014, 99, 749) and in each caseexacerbations contribute to disease progression and reduced survival(Liou et al., Am J Epidemiol., 2001, 153, 345; Soler-Cataluna et al.,Thorax, 2005, 60, 925; Roberts et al., Intern Med J., 2012 42, 129). Themajority of rhinovirus induced exacerbations of COPD are subsequentlyfolllowed by a secondary bacterial infection (Mallia et al., Am. J.Respir. Crit. Care Med., 2012, 186, 1117; George et al., Eur Respir J.,2014; 87). In addition, infection with HRV is one of the factors thatcan direct the infant immune system towards an asthmatic phenotype (D.J. Jackson et al., Am. J. Respir. Crit. Care Med., 2008, 178, 667).

The socioeconomic impact of HRV is enormous and treatment often includesthe inappropriate use of antibiotics. It has been estimated that thecommon cold accounts for at least twenty-five million absences fromwork, and nearly as many school absences, annually in the United States(Rotbart, Antivir. Res., 2002 53, 83). Direct and indirect costs fromthe common cold and related complications in asthmatics alone have beenestimated as high as forty billion dollars annually in the United States(A. M. Fendrick et al., Arch. Intern. Med., 2003, 163, 487.

There are three species of HRV (A, B, and C) comprising more than 150genotypes. HRV-A and —C are most commonly detected and the latterappears to be the more pathogenic group in the paediatric asthma patientpopulation at least (Piralla et al., Journal of Clinical Virology, 2009,45, 311; Bizzintino et al., Eur. Respir. J., 2011, 37, 1037). HRVs canalso be devided into 3 broad groups based on the cellular receptorthrough which cell entry is mediated. The major group of HRVs(approximately 90% of serotype HRV-A and B) enter host cells throughinteraction with the human intracellular adhesion molecule (ICAM-1). Theremaining ˜10% HRV-A and B viruses comprise the minor group and utilizethe low-density lipoprotein receptor for cell entry. The more recentlydiscovered HRV-C species binds to human cadherin-related family member 3(CDHR3) to facilitate entry. HRVs enter the cell by triggeringreceptor-mediated endocytosis, with uncoating occurring in theendosomes. The differences between the serotypes not only prevent thebody from developing cross-immunity, they have greatly impeded thedevelopment of vaccines and other virus-specific methods of preventionand treatment.

The naked HRV RNA genome (˜8 kb) is surrounded by a capsid composed ofsixty copies each of four structural proteins, denoted VP1-VP4, in anicosahedral configuration producing a virus particle of ˜30 nm diameter.HRV replication requires viral RNA-dependant RNA polymerase, as well asmultiple virus and host-cell derived accessory proteins. The HRV genomeis translated as a single polyprotein, which is first cleaved followingtranslation by virus-encoded proteases into three proteins, which arethemselves cleaved to produce at least eleven proteins. Viral genomereplication can begin in as little as one hour following infection, andthe release of nearly one million fully assembled virus particles atcell death can occur in as little as four hours following cell entry.

Currently, there are no medications approved for use in humans that curethe underlying HRV infection. A few attempts to attack HRVs directlyhave shown some promise.4-[2-[1-(6-methyl-3-pyridazinyl)-4-piperidinyl]-ethoxy]benzoate,otherwise known as “pirodavir,” is able to function as a capsid-bindinginhibitor, but problems with solubility, endogenous cleavage, and costhave undermined its utility against HRV. Pleconaril (PICOVIR) was shownto be effective at inhibiting HRV replication, but has been rejected bythe U.S. FDA, citing significant safety concerns. Rupintrivir, a viral3C protease inhibitor was efficacious in experimental HRV challengestudies in humans but was ineffective against naturally occuring HRVinfections (Bauer et al., Current Opinion in Virology, 2017, 24, 1).Certain imidazopyrazines have been suggested as being effectiveantiviral agents against HRV and other viruses; their mode of action isuncertain, though it is suggested that it is not through their effect oncyclin-dependant kinases (U.S. Pub. App. No. 2011/0166147 by Macleod etal.).

In light of the above, there remains a need for new therapeutics againstHRVs and enteroviruses.

Notwithstanding other differences, positive-strand RNA viruses depend ona single fundamental step of RNA-dependent RNA synthesis for viralgenome replication. This step is essential for the viral life cycle andthese viruses are known to further depend on many host proteins to startand maintain RNA-dependent RNA polymerase activity. Without theinteraction of host factors, the viruses would be unable toreplicate/survive. Therefore, a possible therapeutic intervention forinhibiting viral infections of this class is to block the virus-hostinteraction, especially as it concerns viral genome replication. If hostfactors essential for the virus, but not essential for the host, can bemanipulated, then significant inhibition of viral propagation could beachieved. Additionally, host factors with redundancies could representpromising targets for intervention. This would be particularly true iflarge classes of viruses evolved an ability to interact with only one ofa series of redundant host factors. One set of host proteins that arethought to be potential targets for inhibiting viral replication arephosphatidylinositol-4-kinases.

Phosphatidylinositol-4-kinases (PI4K) are involved in several cellularactivities, including membrane fusion, vesicular transport and cellsignaling, through catalysing the phosphorylation ofphosphatidylinositol to form phosphatidylinositol-4 phosphate (PI4P).There are several known isoforms of PI4K which differ across severalproperties, including sequence, size, tissue, cellular localization andfunction.

One type of PI4K, phosphatidylinositol (type Ill)-4-kinase, betapolypeptide (PI4KIIIβ) (also known in the literature asphosphatidylinositol 4-kinase (III) β, Ptdlns 4-kinase (III) β, PI4KB,Pi4kcb, and PI4K92) is thought to be important for controlling localpopulations of PI4P primarily in the golgi network where it is requiredto maintain structural integrity of the organelle. The enzyme has alsobeen detected in the nucleus. PI4KIIIβ has been implicated by recentstudies to be involved in the genomic replication of several RNAviruses, including HRV, enteroviruses 68 and 71, poliovirus, coxsackievirus, hepatitis C virus, bovine kobuvirus, aichi virus, rubella andothers (See, e.g., van der Schaar et al., Antimicrobial Agents andChemotherapy, 57, 4971; Roulin et al., Cell Host & Microbe, 2014, 16,677; Mello et al., Antimicrobial Agents and Chemotherapy 2014, 58, 1546;Jun Sasaki et al., EMBO J. 2011, 31, 754; Hsu et al., CELL 2010, 141,799; Borawski, J. Virology 2009, 83, 10058; Altan-Bonnet et al., TIBS2012, 37, 293). In addition PI4 KB catalytic activity has been shown tobe essential for spike protein mediated cell entry of SARS coronavirus,the virus responsible for severe acute respiratory syndrome (Yang etal., J. Biol. Chem., 2012, 287, 8457). SARS was an epidemic originatingin southern China that involved 8,448 cases and 774 deaths in 37countries between November 2002 and July 2003. The macro-economic impactof the outbreak has been estimated to be between $30 and 100 billion(Smith, Social Science & Medicine, 2006, 63, 3113). The consensus isthat inhibition of PI4 KB could substantially reduce viral replicationin many RNA viruses, and in particular, positive-strand RNA viruses,implicating PI4 KB as a potential target in the development of broadspectrum antiviral agents. In addition, PI4 kinases have roles inbacterial entry and replication, and PI4 KB has been implicated inLegionella pneumophila infection through the role of PI4P in anchoringbacterial proteins to the intracellular legionella containingreplicative vacuole (Clayton et al. Pu PROGRESS IN LIPID RESEARCH 2013,52 294). A PI4 KB inhibitor may thus be effective at counteracting acutelung injury or acute respiratory distress syndrome associated withLegionella infection and possibly as a treatment for other intracellularbacterial infections.

E. P. Keaney et al. (Bioorg. Med. Chem. Lett., 24 (2014) 3714-3718)describes 2-alkyloxazole derivatives as PI4KIIIβ inhibitors for possibletreatment of Hepatitis C viral infections.

I. Medrova et al. (J. Med. Chem., 2017, 60(1), 100-118) describes anumber of imidazo[1,2-b]pyridazine derivatives as PI4KIIIβ inhibitorsfor possible treatment of viral infections.

J. B. Shotwell, in a set of presentation slides entitled “ChemicalOptimization of Novel Inhibitor Classes for PI4KIIIβ: A Critical HostFactor for Enterovirus Replication” submitted to “The 27th InternationalConference on Antiviral Research” (held in Raleigh, N.C., USA) andpresented on 12 May 2014 described a number compounds active at the PI4KB receptor. The slides were predominantly directed to compounds fororal administration and include a slide entitled “Existing Chemotyopeswere optimized for IN Delivery” showing the effect on the lung ofintranasal administration of compound GSK3180404A and compoundGSK3159043A in a rat model. The slide shows substantial accumulation ofcompound in lung tissue in respect of both compounds. The followingslide entitled “Nasal Epithelian Findings Observed following IN dose”contains a series of histological images showing ulceration in the ratnasal cavity and bronchial epithelial hyperplasia in the rat lung fromintranasal administration of GSK3159043.

There exists a need for compounds which are potent PI14KIIIβ inhibitors.There is also a need for compounds which may also be useful as selectivePI4KIIIβ inhibitors.

In particular, there is a need for compounds which are are potentPI4KIIIβ inhibitors and which do not substantially accumulate in bodytissue, e.g. lung tissue, particularly when administered by the inhaledor intranasal routes. Such compounds may be useful in treating orpreventing viral infections and disorders caused or exacerbated by theviral infection, particularly HRV infection.

BRIEF SUMMARY OF THE INVENTION

The invention is directed to compounds of formula (I) orpharmaceutically acceptable salts thereof,

wherein R¹, R², R³, R^(4a), R^(4b), R^(4c), R⁵, W, X, Y and Z aredefined herein.

The compounds of formula (I) have been shown to be selective inhibitorsof PI4KIIIβ and may be useful in treating or preventing viral infectionsand disorders caused or exacerbated by viral infections. Disorders thatare particularly caused or exacerbated by viral infections include COPD,asthma, cystic fibrosis, bronchiectasis and congestive heart failure. Inaddition disorders that are caused or exacerbated by rhinoviralinfections include bronchiolitis, otitis media, sinusitis and acutebronchitis. Also, rhinoviral infections may cause a secondary bacterialinfection in children, the elderly and immunosuppressed. Such asecondary bacterial infection may cause pneumonia.

Accordingly, the invention is further directed to methods of treatmentor prevention of viral infections and disorders caused or exacerbated bythe viral infection, which method comprises administering to a patientin need thereof a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

The invention is further directed to pharmaceutical formulationscomprising a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof and one or morepharmaceutically acceptable excipients.

The invention is further directed to compounds of formula (I) orpharmaceutically acceptable salts thereof for use in therapy.

The invention is further directed to the use of compounds of formula (I)or pharmaceutically acceptable salts thereof in the manufacture of amedicament for the treatment or prevention of viral infections anddisorders caused or exacerbated by the viral infection.

DETAILED DESCRIPTION OF THE INVENTION

According to a first aspect, the invention provides a compound ofgeneral Formula (I) or a pharmaceutically acceptable salt thereof,

-   wherein-   W is C, X is C, Y is N and Z is C;-   W is C, X is N, Y is C and Z is C;-   W is C, X is N, Y is C and Z is N;-   W is N, X is C, Y is C and Z is N; or-   W is N, X is C, Y is C and Z is C;-   R¹ is C₁₋₄alkoxy, —C(═O)N(R^(1a)R^(1b)), —S(═O)₂—N(R^(1a)R^(1b)),    —S(═O)₂—R^(1c) or —S(═O)—R^(1c),-   wherein    -   R^(1a) is C₁₋₃alkyl, haloC₁₋₃alkyl, hydroxyC₁₋₃alkyl,        C₁₋₃alkoxyC₁₋₃alkyl, tetrahydropyranyl or tetrahydrofuranyl;        R^(1b) is H or C₁₋₃alkyl, or R^(1a) and R^(1b), together with        the nitrogen to which they are attached, form a 4- to 7-membered        ring, which ring contains ring-carbon atoms and optionally one        ring-oxygen atom, wherein the ring is a) optionally substituted        by one or two groups selected from C₁₋₃alkyl, halo, C₁₋₃alkoxy,        hydroxy, hydroxyC₁₋₃alkyl and oxo, which may be the same or        different or b) is ortho- or spiro-fused to an unsubstituted 4-6        membered cycloalkane ring or an unsubstituted 4-6 membered        saturated heterocyclic ring; and    -   R^(1c) is C₁₋₃alkyl, C₁₋₃alkoxy, hydroxy, hydroxyC₁₋₃alkyl or        C₁₋₃alkoxyC₁₋₃alkyl;-   R² is H, C₁₋₃alkyl, halo or —O—R^(2a), wherein R^(2a) is H or an    unsubstituted linear C₁₋₃alkyl chain, wherein one or two chain    carbon atoms are optionally replaced by oxygen atoms;-   R³ is H or halo;-   and wherein either-   i) R^(4a) is H, C₁₋₃alkyl or halo R^(4b) is C₁₋₃alkyl, cyclopropyl    or hydroxyC₁₋₂alkyl; or R^(4a) and R^(4b) together with the carbon    to which they are attached form an unsubstituted 3-6 membered    saturated ring containing ring-carbon atoms and optionally a    ring-oxygen atom, wherein the ring is optionally substituted by one    C₁₋₃alkyl group or one hydroxyC₁₋₂alkyl group; and R^(4c) is OH,    hydroxymethyl or hydroxyethyl;-   ii) R^(4a) H, C₁₋₃alkyl, halo or OH; R^(4b) is H, C₁₋₃alkyl or halo    R^(4c) is an unsubstituted ring selected from the list consisting of    oxetanyl, tetrahydrofuranyl and tetrahydropyranyl; or-   iii) R^(4a) is H, and R^(4b) and R^(4c) together with the carbon to    which they are attached form an unsubstituted ring selected from the    list consisting of oxetane, tetrahydrofuran or tetrahydropyran; and-   R⁵ is    -   a) imidazol-2-yl optionally substituted by a C₁₋₃alkyl group at        the 1-position and optionally substituted by a methyl group at        the 5-position; or    -   b) pyrazol-1-yl optionally substituted by a C₁₋₃alkyl group at        the 5-position and optionally substituted by a methyl group at        the 4-position.

In an embodiment W is C, X is N, Z is C and Y is C.

In a further embodiment R^(4c) is OH.

In an embodiment R² is H, C₁₋₃alkyl, chloro or —O—R^(2a), wherein R^(2a)is H or an unsubstituted linear C₁₋₃alkyl chain, wherein one or twochain carbon atoms are optionally replaced by oxygen atoms; and R³ is Hor fluoro.

In another embodiment i) R^(4a) is H, C₁₋₃alkyl or fluoro; R^(4b) isC₁₋₃alkyl, cyclopropyl or hydroxyC₁₋₂alkyl; or R^(4a) and R^(4b)together with the carbon to which they are attached form anunsubstituted 3-6 membered saturated ring containing ring-carbon atomsand optionally a ring-oxygen atom, wherein the ring is optionallysubstituted by one C₁₋₃ alkyl group or one hydroxyC₁₋₂alkyl group; andR^(4c) is OH, hydroxymethyl or hydroxyethyl;

-   -   ii) R^(4a) H, C₁₋₃alkyl, fluoro or OH; R^(4b) is H, C₁₋₃alkyl or        fluoro; R^(4c) is an unsubstituted ring selected from the list        consisting of oxetanyl, tetrahydrofuranyl and tetrahydropyranyl;        or    -   iii) R^(4a) is H, and R^(4b) and R^(4c) together with the carbon        to which they are attached form an unsubstituted ring selected        from the list consisting of oxetane, tetrahydrofuran or        tetrahydropyran.

In an embodiment, the present invention provides compounds of Formula(Ia) or pharmaceutically acceptable salts thereof:

-   -   wherein    -   X is N or C, Y is N or C and Z is N or C; wherein X and Y cannot        both be N or both be C; and wherein when Z is N, X is N and Y is        C;    -   R¹ is C₁₋₄alkoxy, —C(═O)N(R^(1a)R^(1b)),        —S(═O)₂—N(R^(1a)R^(1b)), —S(═O)₂—R^(1c) or —S(═O)—R^(1c),        wherein        -   R^(1a) is C₁₋₃alkyl, haloC₁₋₃alkyl, hydroxyC₁₋₃alkyl or            C₁₋₃alkoxyC₁₋₃alkyl; R^(1b) is H or C₁₋₃alkyl, or R^(1a) and            R^(1b), together with the nitrogen to which they are            attached, form a 4- to 7-membered ring, which ring contains            ring-carbon atoms and optionally one ring-oxygen atom,            wherein the ring is a) optionally substituted by one or two            groups selected from C₁₋₃alkyl, halo, C₁₋₃alkoxy, hydroxy            and oxo, which may be the same or different or b) is ortho-            or spiro-fused to an unsubstituted 4-6 membered cycloalkane            ring or an unsubstituted 4-6 membered saturated heterocyclic            ring; and        -   R^(1c) is C₁₋₃alkyl, C₁₋₃alkoxy, hydroxy, hydroxyC₁₋₃alkyl            or C₁₋₃alkoxyC₁₋₃alkyl;    -   R² is H, C₁₋₃alkyl, chloro or —O—R^(2a), wherein R^(2a) is H or        an unsubstituted linear C₁₋₃alkyl chain, wherein one or two        chain carbon atoms are optionally replaced by oxygen atoms;    -   R³ is H or fluoro;    -   R^(4a) is H or methyl;    -   R^(4b) is C₁₋₃alkyl or hydroxyC₁₋₂alkyl; and    -   R⁵ is        -   a) imidazol-2-yl optionally substituted by a C₁₋₃alkyl group            at the 1-position and optionally substituted by a methyl            group at the 5-position; or        -   b) pyrazol-1-yl optionally substituted by a C₁₋₃alkyl group            at the 5-position and optionally substituted by a methyl            group at the 4-position.

In an embodiment, X is N, Z is C and Y is C.

In an embodiment the compound is a compound of formula (Ib):

In another embodiment the compound is a compound of formula (Ic):

In an embodiment R¹ is —C(═O)N(R^(1a)R^(1b)) or —S(═O)₂—R^(1c). In afurther embodiment R¹ is —C(═O)N(R^(1a)R^(1b)).

In an embodiment R^(1a) is hydroxyC₁₋₃alkyl or tetrahydropyranyl. In anembodiment R^(1a) is hydroxyC₁₋₃alkyl. In a further embodiment R^(1a) is3-hydroxy-1-propyl, 2-hydroxy-1-ethyl, 3-hydroxy-2-propyl or4-tetrahydropyranyl.

In an embodiment R^(1b) is C₁₋₃alkyl. In a further embodiment R^(1b) ismethyl or ethyl.

In a further embodiment R^(1a) is hydroxyC₁₋₃alkyl and R^(1b) isC₁₋₃alkyl. In a further embodiment R^(1a) is 3-hydroxy-1-propyl andR^(1b) is C₁₋₃alkyl. In a further embodiment R^(1a) is3-hydroxy-2-propyl and R^(1b) is C₁₋₃alkyl. In a further embodimentR^(1a) is 3-hydroxy-1-propyl and R^(1b) is methyl. In a furtherembodiment R^(1a) is 3-hydroxy-2-propyl and R^(1b) is methyl. In afurther embodiment R^(1a) is 2-hydroxy-1-ethyl and R^(1b) is ethyl. In afurther embodiment R^(1a) is 3-hydroxy-2-propyl and R^(1b) is methyl. Ina further embodiment R^(1a) is 4-tetrahydropyranyl and R^(1b) is methyl.

In an embodiment R^(1a) and R^(1b), together with the nitrogen to whichthey are attached, form a 4- to 7-membered saturated ring, which ringcontains ring-carbon atoms and optionally one ring-oxygen atom, whereinthe ring is a) optionally substituted by one or two groups selected fromC₁₋₃alkyl, halo, C₁₋₃alkoxy, hydroxy, hydroxyC₁₋₃alkyl and oxo, whichmay be the same or different or b) is ortho- or spiro-fused to anunsubstituted 4-6 membered cycloalkane ring or an unsubstituted 4-6membered saturated heterocyclic ring.

In an embodiment R^(1a) and R^(1b), together with the nitrogen to whichthey are attached, form an optionally substituted pyrrolidine ring. In afurther embodiment the pyrrolidine ring is substituted by C₁₋₃ alkyl,hydroxy or hydroxyC₁₋₃alkyl.

In an embodiment R^(1c) is hydroxyC₁₋₃alkyl. In a further embodimentR^(1c) is 2-hydroxy-1-ethyl.

In an embodiment R² is C₁₋₃alkyl, chloro or —O—R^(2a). In a furtherembodiment R² is C₁₋₃ alkyl, chloro or methoxy.

In an embodiment, R³ is H or fluoro; In a further embodiment, R³ is H.

In an embodiment R^(4a) is methyl.

In an embodiment R^(4b) is C₁₋₃alkyl. In a further embodiment, R^(4b) ismethyl or ethyl. In a further embodiment R^(4b) is methyl.

In an embodiment, R^(4a) is methyl and R^(4b) is methyl.

In an embodiment, R^(4a) is C₁₋₃alkyl, R^(4b) is C₁₋₃alkyl and R^(4c) isOH. In a further embodiment, R^(4a) is methyl, R^(4b) is methyl andR^(4c) is OH.

In an embodiment R⁵ is imidazol-2-yl optionally substituted by aC₁₋₃alkyl group at the 1-position and optionally substituted by a methylgroup at the 5-position. In a further embodiment R⁵ is1-methyl-1H-imidazol-2-yl.

In an embodiment the compound is a compound according to Formula (I)and:

-   W is C, X is N, Z is C and Y is C;-   R¹ is —C(═O)N(R^(1a)R^(1b)) or —S(═O)₂—R^(1c), wherein Ria is    hydroxyC₁₋₃alkyl and R^(1b) is C₁₋₃alkyl; or R^(1a) and R^(1b),    together with the nitrogen to which they are attached, form an    optionally substituted pyrrolidine ring; and wherein R^(1c) is    hydroxyC₁₋₃alkyl;-   R² is C₁₋₃alkyl, chloro or —O—R^(2a);-   R³ is H;-   R^(4a) is methyl;-   R^(4b) is C₁₋₃alkyl;-   R^(4c) is OH; and-   R⁵ is imidazol-2-yl optionally substituted by a C₁₋₃alkyl group at    the 1-position and optionally substituted by a methyl group at the    5-position.

In an embodiment the compound is a compound according to Formula (I)and:

-   W is C, X is N, Z is C and Y is C;-   R¹ is —C(═O)N(R^(1a)R^(1b)) wherein R^(1a) is hydroxyC₁₋₃alkyl and    R^(1b) is C₁₋₃alkyl; or R^(1a) and R^(1b), together with the    nitrogen to which they are attached, form an optionally substituted    pyrrolidine ring substituted by C₁₋₃ alkyl, hydroxy or    hydroxyC₁₋₃alkyl;-   R² is C₁₋₃alkyl, chloro or methoxy;-   R³ is H;-   R^(4a) is methyl;-   R^(4b) is methyl;-   R^(4c) is OH; and-   R⁵ is 1-methyl-1H-imidazol-2-yl.

In an embodiment, the compound of formula (I) is selected from the groupconsisting of:

-   2-chloro-N-ethyl-N-(2-hydroxyethyl)-5-(5-(1-hydroxyethyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide    (Compound 15);-   5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide    (Compound 17);-   N-ethyl-N-(2-hydroxyethyl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxybenzamide    (Compound 19);-   (S)—N-(1-hydroxypropan-2-yl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxy-N-methylbenzamide    (Compound 20);-   5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide    (Compound 21);-   (S)—N-(1-hydroxypropan-2-yl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,2-dimethylbenzamide    (Compound 22);-   (R)-(2-(hydroxymethyl)pyrrolidin-1-yl)(5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylphenyl)methanone    (Compound 25);-   (S)-(5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylphenyl)(3-hydroxypyrrolidin-1-yl)methanone    (Compound 29);-   5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-2-methoxy-N-methylbenzamide    (Compound 32); and-   (R)-(2-(hydroxymethyl)pyrrolidin-1-yl)(5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyphenyl)methanone    (Compound 36);-   N-ethyl-N-(2-hydroxyethyl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzamide    (Compound 38);-   N-(2-hydroxyethyl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,2-dimethylbenzamide    (Compound 43);-   5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,2-dimethyl-N-(tetrahydrofuran-3-yl)benzamide    (Compound 59);-   5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(2-hydroxypropyl)-N,2-dimethylbenzamide,    isomer 1 (Compound 62);-   5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(2-hydroxypropyl)-N,2-dimethylbenzamide,    isomer 2 (Compound 63);-   2-Chloro-N-(2-hydroxyethyl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide    (Compound 37);-   N—((S)-1-Hydroxypropan-2-yl)-5-(5-(1-hydroxypropyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin3-yl)-N,2-dimethylbenzamide,    isomer 1 (Compound 80);-   N—((S)-1-Hydroxypropan-2-yl)-5-(5-(1-hydroxypropyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin3-yl)-N,2-dimethylbenzamide,    isomer 2 (Compound 81);-   5-(5-(1-Hydroxybutan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide,    isomer 1 (Compound 66); and-   5-(5-(1-Hydroxybutan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide    isomer 2 (Compound 67);    or a pharmaceutically acceptable salt of any of the above.

In an embodiment the compound of formula (I) is5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide(Compound 17)

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of formula (I) isN-ethyl-N-(2-hydroxyethyl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxybenzamide(Compound 19)

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of formula (I) is5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide(Compound 21)

or a pharmaceutically acceptable salt thereof.

In an embodiment the compound of formula (I) is(S)—N-(1-hydroxypropan-2-yl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,2-dimethylbenzamide(Compound 22)

or a pharmaceutically acceptable salt thereof.

Terms and Definitions

Alkyl is a univalent radical derived by removal of a hydrogen atom froman acyclic alkane. For example, a C₁₋₄alkyl is alkyl comprising from 1to 4 carbon atoms. Alkyl may be straight chain or branched chain.Examples of C₁₋₄alkyl are methyl, ethyl, n-propyl, n-butyl, iso-propyl,iso-butyl, sec-butyl and tert-butyl.

Alkoxy is a group of formula “—O—R” where R is alkyl (as definedhereinbefore). For example, C₁₋₄alkoxy is alkoxy consisting of 1 to 4carbon atoms. Examples of C₁₋₄alkoxy are methoxy, ethoxy, n-propoxy,n-butoxy, iso-propoxy, iso-butoxy, sec-butoxy and tert-butoxy.

Halo refers to a halogen radical, i.e. fluoro, chloro, bromo or iodo.

Haloalkyl is alkyl (as defined hereinbefore) substituted by one or morehalo (as defined hereinbefore), which halo may be the same or different.For example, haloC₁₋₃alkyl is haloalkyl consisting of 1 to 3 carbonatoms. Examples of haloC₁₋₃alkyl are monofluoromethyl, difluoromethyl,trifluoromethyl and 1-chloro-2-fluoroethyl.

Hydroxyalkyl is alkyl (as defined hereinbefore) substituted by one ormore hydroxy substiutents. For example, hydroxyC₃alkyl is of formula—(CH₂)₃OH (where the “-” indicates which atom is attached to thecompound of Formula (I)).

Alkoxyalkyl is alkyl (as defined hereinbefore) substituted by one ormore alkoxy substituents. For example, C₃alkoxyC₂alkyl is of formula—(CH₂)₂O(CH₂)₂CH₃ (where the “-” indicates which atom is attached to thecompound of Formula (I)).

Oxo is a bivalent radical of formula ═O.

A 4-6 membered saturated heterocyclic ring is monocyclic and consists ofring-carbon atoms and ring-heteroatoms selected from the group nitrogen,oxygen and sulfur. In an embodiment, the heterocyclic ring consists of 1or 2 ring-heteroatoms. Examples are pyrrolidine, dioxolane,imidazolidine, pyrazolidine, piperidine, dioxane, morpholine, dithiane,thiomorpholine and piperazine.

A 4-6 membered cycloalkane ring does not contain any ring-heteroatomsand is saturated and monocyclic. Examples are cyclobutane, cyclopentaneand cyclohexane.

An ‘ortho-fused ring system’ comprises two rings having only two atomsand one bond in common, for example

A ‘spiro-fused ring system’ comprises two rings joined at the samecarbon, for example

‘Substituted’ in reference to a group indicates that a hydrogen atomattached to a member atom within a group is replaced. It should beunderstood that the term ‘substituted’ includes the implicit provisionthat such substitution be in accordance with the permitted valence ofthe substituted atom and the substituent and that the substitutionresults in a stable compound (i.e. one that does not spontaneouslyundergo transformation such as rearrangement, cyclisation, orelimination). In certain embodiments, a single atom may be substitutedwith more than one substituent as long as such substitution is inaccordance with the permitted valence of the atom. Suitable substituentsare defined herein for each substituted or optionally substituted group.

‘Pharmaceutically acceptable’ refers to those compounds, materials,formulations, and dosage forms which are, within the scope of soundmedical judgment, suitable for use in contact with the tissues of humanbeings and animals without excessive toxicity, irritation, or otherproblem or complication, commensurate with a reasonable benefit/riskratio.

Throughout the description and the claims which follow, unless thecontext requires otherwise, the word ‘comprise’, and variations such as‘comprises’ and ‘comprising’, will be understood to imply the inclusionof a stated integer or step or group of integers but not to theexclusion of any other integer or step or group of integers or steps.

The compounds of formula (I) and formula (Ia) and pharmaceuticallyacceptable salts thereof may exist in solid or liquid form. In the solidstate, they may exist in crystalline or non-crystalline form, or as amixture thereof. When in crystalline form, the skilled artisan willappreciate that pharmaceutically acceptable solvates may be formedwherein solvent molecules are incorporated into the crystalline latticeduring crystallization. Solvates may involve non-aqueous solvents suchas ethanol, iso-propyl alcohol, N,N-dimethylformamide (DMF),dimethylsulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate,or they may involve water as the solvent that is incorporated into thecrystalline lattice. Solvates wherein water is the solvent that isincorporated into the crystalline lattice are typically referred to as‘hydrates’. Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water.

Compounds of formula (I) and formula (Ia) and pharmaceuticallyacceptable salts thereof that exist in crystalline form, including thevarious solvates thereof, may exhibit polymorphism (i.e. the capacity tooccur in different crystalline structures). These different crystallineforms are typically known as ‘polymorphs’. The invention includes allsuch polymorphs. Polymorphs have the same chemical composition butdiffer in packing, geometrical arrangement, and other descriptiveproperties of the crystalline solid state. Polymorphs, therefore, mayhave different physical properties such as shape, density, hardness,deformability, stability, and dissolution properties. Polymorphstypically exhibit different melting points, IR spectra, and X-ray powderdiffraction patterns, which may be used for identification. It will beappreciated that different polymorphs may be produced, for example, bychanging or adjusting the reaction conditions or reagents, used inmaking the compound. For example, changes in temperature, pressure, orsolvent may result in polymorphs. In addition, one polymorph mayspontaneously convert to another polymorph under certain conditions.

The invention also includes isotopically-labelled compounds, which areidentical to the compounds of formula (I) and formula (Ia) andpharmaceutically acceptable salts thereof, but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number most commonly found innature.

Examples of isotopes that can be incorporated into the compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen andfluorine, such as ³H, ¹¹C, ¹⁴C and ¹⁸F.

The compounds according to formula (I) and formula (Ia) may contain oneor more asymmetric centres (also referred to as a chiral centres) andmay, therefore, exist as individual enantiomers, diastereoisomers, orother stereoisomeric forms, or as mixtures thereof. Chiral centres, suchas chiral carbon atoms, may also be present in a substituent such as analkyl group. Where the stereochemistry of a chiral centre present informula (I), or in any chemical structure illustrated herein, is notspecified, the structure is intended to encompass any stereoisomer andall mixtures thereof. Thus, compounds according to formula (I)containing one or more chiral centres may be used as racemicmodifications including racemic mixtures and racemates,enantiomerically-enriched mixtures, or as enantiomerically-pureindividual stereoisomers.

Individual stereoisomers of a compound according to formula (I) andformula (Ia) which contain one or more asymmetric centres may beresolved by methods known to those skilled in the art. For example, suchresolution may be carried out (1) by formation of diastereoisomericsalts, complexes or other derivatives; (2) by selective reaction with astereoisomer-specific reagent, for example by enzymatic oxidation orreduction; or (3) by gas-liquid or liquid chromatography in a chiralenvironment, for example, on a chiral support such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where the desired stereoisomer is converted intoanother chemical entity by one of the separation procedures describedabove, a further step is required to liberate the desired form.Alternatively, specific stereoisomers may be synthesised by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer to the other by asymmetrictransformation.

It is to be understood that the references herein to a compound offormula (I) and formula (Ia) or a pharmaceutically acceptable saltthereof includes a compound of formula (I) and formula (Ia) respectivelyas a free base, or as a pharmaceutically acceptable salt thereof. Thus,in one embodiment, the invention is directed to a compound of formula(I). In another embodiment, the invention is directed to apharmaceutically acceptable salt of a compound of formula (I).

Pharmaceutically acceptable salts include, amongst others, thosedescribed in Berge, J. Pharm. Sci., 1977, 66, 1-19, or those listed in PH Stahl and C G Wermuth, editors, Handbook of Pharmaceutical Salts;Properties, Selection and Use, Second Edition Stahl/Wermuth:Wiley-VCH/VHCA, 2011

Non-pharmaceutically acceptable salts may be used, for example asintermediates in the preparation of a compound of formula (I) or formula(Ia) or a pharmaceutically acceptable salt thereof. Alternativelynon-pharmaceutically acceptable salts of formula (I) and formula (Ia)are included herein.

Suitable pharmaceutically acceptable salts can include acid additionsalts.

Such acid addition salts can be formed by reaction of a compound offormula (I) or formula (Ia) (which, for example contains a basic amineor other basic functional group) with the appropriate acid, optionallyin a suitable solvent such as an organic solvent, to give the salt whichcan be isolated by a variety of methods, including crystallisation andfiltration.

Salts may be prepared in situ during the final isolation andpurification of a compound of formula (I) or formula (Ia). If a basiccompound of formula (I) or formula (Ia) is isolated as a salt, thecorresponding free base form of that compound may be prepared by anysuitable method known to the art, including treatment of the salt withan inorganic or organic base.

It will be understood that if a compound of formula (I) or formula (Ia)contains two or more basic moieties, the stoichiometry of salt formationmay include 1, 2 or more equivalents of acid. Such salts would contain1, 2 or more acid counterions, for example, a dihydrochloride salt.Stoichiometric and non-stoichiometric forms of a pharmaceuticallyacceptable salt of a compound of formula (I) or formula (Ia) areincluded within the scope of the invention, including sub-stoichiometricsalts, for example where a counterion contains more than one acidicproton.

Representative pharmaceutically acceptable acid addition salts include,but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate,ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate,bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate(camsylate), caprate (decanoate), caproate (hexanoate), caprylate(octanoate), cinnamate, citrate, cyclamate, digluconate,2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate(ethylenediaminetetraacetate), estolate (lauryl sulfate),ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate,fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate),glucoheptonate (gluceptate), gluconate, glucuronate, glutamate,glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate,hydrabamine (N,N′-di(dehydroabietyl)-ethylenediamine), hydrobromide,hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate,lactobionate, laurate, malate, maleate, malonate, mandelate,methanesulfonate (mesylate), methylsulfate, mucate,naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate(napsylate), nicotinate, nitrate, oleate, palmitate,p-aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate),pantothenate, pectinate, persulfate, phenylacetate,phenylethylbarbiturate, phosphate, polygalacturonate, propionate,p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate,sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate,tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide,undecanoate, undecylenate, and valerate.

Compounds of formula (I) or formula (Ia) and their salts andpharmaceutically acceptable salts thereof including solvates (includinghydrates), complexes, polymorphs, prodrugs, radiolabelled derivativesand stereoisomers of the compounds of formula (I) or formula (Ia) andtheir pharmaceutically acceptable salts, are referred to hereinafter as“compounds of the invention”.

General Routes

Compounds of the invention may be prepared in a variety of ways. In thefollowing reaction schemes and hereafter, unless otherwise stated R¹ toR⁵, R^(4a), R^(4b), R^(4c), R⁵, W, X, Y and Z are as defined in thefirst aspect. Throughout the specification, general formulae aredesignated by Roman numerals (I), (II), (III), (IV) etc.

General Route to Formula (I)

Compounds for formula (Ix), i.e. compounds of formula (I) where R^(4a)is H and R^(4c) is OH, may be prepared according to reaction scheme 1 bytreating (II) with a suitable Grignard reagent (such as methylmagnesiumbromide) in a solvent (for example THF) followed by deprotection with asuitable acid (for example 4 M HCl in 1,4-dioxane) in a solvent (forexample methanol).

Compounds of formula (II) may be prepared according to reaction scheme 2by treating compounds of formula (III) with a boronic ester (for example2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethan-1-ol)in a solvent (for example 1,4-dioxane and water) in the presence of acatalyst [for example PdCl₂(dppf)] and a base (for example potassiumfluoride).

Compounds of formula (III) may be prepared according to reaction scheme3 from compounds of formula (IV) by treatment of (IV) with a suitableoxidising agent (for example DMP) in a solvent (for example DCM).

Compounds of formula (IV) may be prepared according to reaction scheme 4from compounds of formula (V). Firstly the amine is protected with anappropriate amine protecting group (for example tert-butylcarbamate viatreatment with appropriate reagents for example di-tert-butyldicarbonate, DIPEA and DMAP in DCM). Secondly the ester is reduced tothe primary alcohol with a suitable reducing agent (for example sodiumborohydride) in a solvent (for example ethanol).

Compounds of formula (V) may be prepared according to reaction scheme 5from compounds of formula (VI) (where L is Cl or Br or a mixture ofcompounds of formula (VI) where L is Cl and Br) by treatment with anamine (for example (3-(1-methyl-1H-imidazol-2-yl)phenyl)methylamine) anda base (for example DIPEA) in a solvent (for example DMSO).

Compounds of formula (Ix′), i.e. compounds of formula (I) where R^(4a)and R^(4b) are C₁₋₃alkyl and R^(4c) is OH, may be prepared according toreaction scheme 6 by treating (VII) with boronic ester (for exampleN-(3-hydroxypropyl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide)in the presence of a catalyst [for example PdCl₂(dppf)] in solvent (forexample 1,4-dioxane and water) with base (for example sodium carbonate).

Compounds of formula (VII) may be prepared from compounds of formula (V)according to reaction scheme 7 by treating (V) with a Grignard reagent(for example methylmagnesium bromide) in a solvent (for example DCM).For the preparation of (V) see Scheme 5.

Compounds of formula (VIa). i.e. compounds of formula (VI) (see scheme5) where W is C, X is N, Y is C, Z is C and L is Cl, may be preparedaccording to reaction scheme 8. Firstly compounds of formula (VIII) maybe obtained by condensation of esters (for example the sodium salt ofdiethyl oxalacetate) and compounds of formula (IX) using an acid (suchas HCl) in a solvent (such as ethanol) with heat (for example 85° C.) togive compounds of formula (VIII). Secondly treatment of (VIII) with achlorinating reagent (for example POCl₃) with heat (for example at 90°C.) gives compounds of formula (X). Treatment of compounds of formula(X) with an iodine or bromine source [for example N-iodosuccinimide(NIS) or N-bromosuccinimide (NBS)] in a solvent (for example DCM) givescompounds of formula (VIa).

A mixture of compounds of formula (VIb), i.e. compounds of formula (VI)(see scheme 5) where W is C, X is C, Y is N, Z is C and L is Cl and Br,may be prepared according to reaction scheme 9 in a number of steps fromcompounds (XI). Firstly compounds of formula (XI) are treated with abrominating agent for example N-bromosuccinimide and sodium bicarbonatein a solvent (for example methanol) to give compounds of formula (XII).Secondly, treating compounds of formula (XII) with 1-chloropropan-2-oneat elevated temperature (for example at 90° C.) gives a mixture ofcompounds of formula (XIII). Iodination or bromination of a mixture ofcompounds of formula (XIII) with, for example N-iodosuccinimide orN-bromosuccinimide, in a solvent (for example DMF) gives the mixture ofcompounds of formula (VIb).

Compounds of formula (VIc), i.e. compounds of formula (VI) (see scheme5) where W is C, X is N, Y is C, Z is N and L is Cl, may be prepared ina number of steps from compounds of formula (XIV) according to reactionscheme 10. Firstly, compounds of formula (XIV) may be reacted withmethyl cyanoformate to give compounds of formula (XV). Secondly,compounds of formula (XV) may be cyclised using carbonyldiimidazole in asolvent (for example DMSO) or alternatively using diethyl carbonate insodium ethoxide and ethanol to give compounds of formula (XVI).Compounds of formula (XVI) may then be chlorinated using for examplePOCl₃, with heat (for example at 90° C.) to give compounds of formula(XVII). Iodination (using for example N-iodosuccinimide) or bromination(using for example N-bromosuccinimide), in a solvent (for example DMF)gives the compounds of formula (VIc).

Compounds of formula (Ix″), i.e. compounds of formula (I) where R^(4c)is hydroxymethyl, may be prepared according to reaction scheme 11 fromcompounds of formula (XVIII).

Compounds of formula (XVIIIa), i.e. compounds of formula (XVIII) where Wis C, X is N, Y is C and Z is C, may be prepared according to reactionscheme 12.

Compounds of formula (XVIIIb), i.e. compounds of formula (XVIII) (fromScheme 11) where W is N, X is C and Y is C, may be prepared fromcompounds of formula (XIX) according to reaction scheme 13.

Alternatively compounds of formula (Ia) (see Scheme 1) may be preparedfrom compounds of formula (V) (see Scheme 4) according to reactionscheme 14. Compounds of formula (Ia) may be resolved into individualenantiomers using techniques familiar to the skilled chemist, forexample chiral HPLC.

Compounds of formula (Id), i.e. compounds of general formula (I) whereR^(4a) and R^(4b) together with the carbon to which they are attachedform a cyclopropane ring substituted by one group R which is a C₁₋₃alkylgroup, may be prepared according to reaction scheme 15A from compoundsof formula (XXa). In reaction scheme 15A, PG is a protecting group suchas tert-butyloxycarbonyl and [Si] is a silicon-based alcohol protectinggroup such as TBDMS.

Compounds of formula (Ie), i.e. compounds of formula (I) where R^(4a) isH and R^(4b) and R^(4c) together with the carbon to which they areattached form an unsubstituted tetrahydropyran ring, may be preparedfrom compounds of formula (XXI) according to reaction scheme 15B.

Compounds of formula (XXI) may be prepared from compounds of formula(XXII) according to reaction scheme 16.

It will be appreciated by the skilled chemist that compounds of formula(I) may also be prepared by elaboration at R¹ as the last step. Inreaction scheme 17, compounds of formula (If) i.e. compounds of formula(I) where R¹ is —C(═O)N(R^(1a)R^(1b)), may be prepared from compounds offormula (XXIII).

It will be appreciated by the skilled chemist that compounds of formula(I) may be converted to other compounds of formula (I) by methods knownin the art. In addition, intermediate compounds described in thereaction schemes above may be converted to other intermediates and thenconverted using the methods described to provide compounds of formula(I). It will also be appreciated that compounds of formula (I) may beprepared using a different sequence of the transformations described inthe reaction schemes, including incorporation of protection/deprotectionsteps where appropriate.

General Route to Formula (Ia)

Compounds of formula (Ix*), i.e. compounds of formula (Ia) where R^(4a)is H, may be prepared according to reaction scheme 1* by treating (IIa*)with a suitable Grignard reagent (such as methylmagnesium bromide) in asolvent (for example THF) followed by deprotection with a suitable acid(for example 4 M HCl in 1,4-dioxane) in a solvent (for examplemethanol).

Compounds of formula (IIa*) may be prepared according to reaction scheme2a* by treating compounds of formula (IIIa*) with a boronic ester (forexample2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethan-1-ol)in a solvent (for example 1,4-dioxane and water) in the presence of acatalyst (for example PdCl₂(dppf)) and a base (for example potassiumfluoride).

Compounds of formula (III*) may be prepared according to reaction scheme3* from compounds of formula (IV*) by treatment of (IV*) with a suitableoxidising agent (for example DMP) in a solvent (for example DCM).

Compounds of formula (IV*) may be prepared according to reaction scheme4* from compounds of formula (V*). Firstly the amine is protected withan appropriate amine protecting group (for example tert-butylcarbamatevia treatment with appropriate reagents for example di-tert-butyldicarbonate, DIPEA and DMAP in DCM). Secondly the ester is reduced tothe primary alcohol with a suitable reducing agent (for example sodiumborohydride) in a solvent (for example ethanol).

Compounds of formula (V*) may be prepared according to reaction scheme5* from compounds of formula (VI*) (where L is Cl or Br or a mixture ofcompounds of formula (VI) where L is Cl and Br) by treatment with anamine (for example (3-(1-methyl-1H-imidazol-2-yl)phenyl)methylamine) anda base (for example DIPEA) in a solvent (for example DMSO).

Compounds of formula (Ib*), i.e. compounds of formula (I*) where R^(4a)and R^(4b) are methyl, may be prepared according to reaction scheme 6 bytreating (VII*) with boronic ester (for exampleN-(3-hydroxypropyl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide)in the presence of a catalyst (for example PdCl₂(dppf)) in solvent (forexample 1,4-dioxane and water) with base (for example sodium carbonate).

Compounds of formula (VII*) may be prepared from compounds of formula(V*) according to reaction scheme 7* by treating (V*) with a Grignardreagent (for example methylmagnesium bromide) in a solvent (for exampleDCM).

Compounds of formula (Via*). i.e. compounds of formula (VI*) (see scheme5*) where X is N, Y is C, Z is C and L is Cl, may be prepared accordingto reaction scheme 8*. Firstly compounds of formula (VIII*) may beobtained by condensation of esters (for example the sodium salt ofdiethyl oxalacetate) and compounds of formula (IX*) using an acid (suchas HCl) in a solvent (such as ethanol) with heat (for example 85° C.) togive compounds of formula (VIII*). Secondly treatment of (VIII*) with achlorinating reagent (for example POCl₃) with heat (for example at 90°C.) gives compounds of formula (X*). Treatment of compounds of formula(X*) with an iodine source (for example NIS) in a solvent (for exampleDCM) gives compounds of formula (Via*).

A mixture of compounds of formula (VIb*), i.e. compounds of formula(VI*) (see scheme 5*) where X is C, Y is N, Z is C and L is Cl and Br,may be prepared according to reaction scheme 9 in a number of steps fromcompounds (XI*). Firstly compounds of formula (XI*) are treated with abrominating agent for example N-bromosuccinimide and sodium bicarbonatein a solvent (for example methanol) to give compounds of formula (XII*).Secondly, treating compounds of formula (XII*) with 1-chloropropan-2-oneat elevated temperature (for example at 90° C.) gives a mixture ofcompounds of formula (XIII*). Iodination of a mixture of compounds offormula (XIII*) with, for example N-iodosuccinimide, in a solvent (forexample DMF) gives the mixture of compounds of formula (VIb*).

Compounds of formula (Vic*), i.e. compounds of formula (VI*) (see scheme5*) where X is N, Y is C, Z is N and L is Cl, may be prepared in anumber of steps from compounds of formula (XIV*) according to reactionscheme 10*. Firstly, compounds of formula (XIV*) may be reacted withmethyl cyanoformate to give compounds of formula (XV*). Secondly,compounds of formula (XV*) may be cyclised using carbonyldiimidazole ina solvent (for example DMSO) or alternatively using diethyl carbonate insodium ethoxide and ethanol to give compounds of formula (XVI*).Compounds of formula (XVI*) may then be chlorinated using for examplePOCl₃, with heat (for example at 90° C.) to give compounds of formula(XVII*). Iodination using for example N-iodosuccinimide, in a solvent(for example DMF) gives the compounds of formula (Vic*).

It will be appreciated by the skilled chemist that compounds of formula(Ia) may be converted to other compounds of formula (Ia) by methodsknown in the art. In addition, intermediate compounds described in thereaction schemes above may be converted to other intermediates and thenconverted using the methods described to provide compounds of formula(Ia). It will also be appreciated that compounds of formula (Ia) may beprepared using a different sequence of the the transformations describedin the reaction schemes, including incorporation ofprotection/deprotection steps where appropriate.

Methods of Use

The compounds of the invention have been shown to be potent inhibitorsof PI4KIIIβ. Further the compounds of the inventon are selectiveinhibitors of PI4KIIIβ. Compounds of the invention may be useful intreating or preventing viral infections and disorders caused orexacerbated by viral infections. Disorders that are particularly causedor exacerbated by viral infections include COPD, asthma, cysticfibrosis, bronchiectasis, congestive heart failure, acute respiratorydistress syndrome and acute lung injury. In addition disorders that arecaused or exacerbated by rhinoviral infections include bronchiolitis,otitis media, sinusitis and acute bronchitis. Also, rhinoviralinfections may cause a secondary bacterial infection in children, theelderly and immunosuppressed. Such a secondary bacterial infection maycause pneumonia.

As used herein, ‘treat’, ‘treatment’ or ‘treating’ in reference to adisorder means: (1) to ameliorate the disorder or one or more of thebiological manifestations of the disorder; (2) to interfere with (a) oneor more points in the biological cascade that leads to or is responsiblefor the disorder, or (b) one or more of the biological manifestations ofthe disorder; (3) to alleviate one or more of the symptoms or effectsassociated with the disorder; or (4) to slow the progression of thedisorder or one or more of the biological manifestations of thedisorder.

As used herein, ‘patient’ refers to a human (including adults andchildren) or other animal. In one embodiment, ‘patient’ refers to ahuman.

It is envisaged that the compounds of the invention may be administeredtopically, for example by inhalation or intranasally. Inhalation refersto administration into the patient's lungs whether inhaled through themouth or through the nasal passages. In one embodiment, the compounds offormula (I) or pharmaceutically acceptable salts thereof may beadministered topically. In another embodiment, the compounds of formula(I) or pharmaceutically acceptable salts thereof may be administered byinhalation. In a further embodiment, the compounds of formula (I) orpharmaceutically acceptable salts thereof may be administeredintranasally. In a further embodiment, the compounds of formula (I) orpharmaceutically acceptable salts thereof may be administeredintraoculaly. In a further embodiment, the compounds of formula (I) orpharmaceutically acceptable salts thereof may be administered aurally.

The compounds of the invention may be administered once per day oraccording to a dosing regimen wherein a number of doses are administeredat varying intervals of time for a given period of time. For example,doses may be administered one, two, three, or four times per day. In oneembodiment, a dose is administered once per day. In a furtherembodiment, a dose is administered twice per day. Doses may beadministered until the desired therapeutic effect is achieved orindefinitely to maintain the desired therapeutic effect. Suitable dosingregimens for a compound of the invention depend on the pharmacokineticproperties of that compound, such as absorption, distribution, andhalf-life, which can be determined by the skilled artisan. In addition,suitable dosing regimens, including the duration such regimens areadministered, for a compound of the invention depend on the disorderbeing treated, the severity of the disorder being treated, the age andphysical condition of the patient being treated, the medical history ofthe patient to be treated, the nature of concurrent therapy, the desiredtherapeutic effect, and like factors within the knowledge and expertiseof the skilled artisan. It will be further understood by such skilledartisans that suitable dosing regimens may require adjustment given anindividual patient's response to the dosing regimen or over time asindividual patient needs change.

Typical daily dosages for inhaled administration range from 0.2 μg to0.02 mg per kg of total body weight, for example from 0.5 μg to 0.01 mgper kg of total body weight. For example, daily dosages for inhaledadministration may be from 20 μg to 2.0 mg per patient, such as 50 μg to1.0 mg per patient.

Additionally, the compounds of the invention may be administered asprodrugs. As used herein, a ‘prodrug’ of a compound of the invention isa functional derivative which, upon administration to a patient,liberates the compound of the invention in vivo. Administration of acompound of the invention as a prodrug may enable the skilled artisan todo one or more of the following: (a) modify the onset of the activity ofthe compound in vivo; (b) modify the duration of action of the compoundin vivo; (c) modify the transportation or distribution of the compoundin vivo; (d) modify the solubility of the compound in vivo; and (e)overcome a side effect or other difficulty encountered with thecompound. Typical functional derivatives used to prepare prodrugsinclude modifications of the compound that are chemically orenzymatically cleavable in vivo. Such modifications, which include thepreparation of phosphates, amides, esters, thioesters, carbonates, andcarbamates, are well known to those skilled in the art.

While not wanting to be bound by any particular theory, it is thoughtthat the compounds of the invention are able to inhibit the activity ofthe host cellular enzyme, PI4KIIIβ and thereby reduce the ability of thevirus to replicate inside a host cell. Many viruses use PI4K to generatemembranes enriched in phosphatidylinositol-4-phosphate (PI4P), which canbe used as replication platforms. Viral replication machinery isassembled on these platforms as a supramolecular complex and the PI4Plipids help to enable viral RNA synthesis. Such intracellular lipidplatforms create a more favorable environment for the virus toefficiently replicate itself. By disrupting the ability of the virus toutilize PI4Ks, and PI4KIIIβ in particular, to create these lipidplatforms and facilitate viral replication, viral infections can betreated and/or prevented.

Therefore according to a further aspect, the invention thus provides amethod of treating a viral infection comprising administering a compoundof formula (I), or a pharmaceutically acceptable salt thereof, to apatient in need thereof.

According to a further aspect, the invention provides a method oftreating a disorder caused or exacerbated by a viral infectioncomprising administering a compound of formula (I), or apharmaceutically acceptable salt thereof, to a patient in need thereof.

According to a further aspect, the invention provides a method oftreating a secondary bacterial infection caused by a viral infectioncomprising administering a compound of formula (I), or apharmaceutically acceptable salt thereof, to a patient in need thereof.

According to a further aspect, the invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use intherapy.

According to a further aspect the invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof for use inthe treatment of a viral infection.

According to a further aspect the invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof for use inthe treatment of a disorder caused or exacerbated by a viral infection.In an embodiment, the disorder is COPD, cystic fibrosis, bronchiectasis,asthma or congestive heart failure. In a further embodiment, thedisorder is COPD or asthma. In a still further embodiment, the disorderis COPD.

According to a further aspect the invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof for use inthe treatment of a secondary bacterial infection caused by a bacterialinfection.

According to a further aspect the invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for treating a viral infection.

According to a further aspect the invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for treating a disorder caused orexacerbated by a viral infection.

According to a further aspect the invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for treating a secondary bacterialinfection caused by a viral infection.

In certain patients such as those with a compromised immune system orcardiopulmonary co-morbidities who have a heightened risk of severeillness following viral infection, it is envisaged that the compounds ofthe invention may be administered prophylactically so as to preventinfection taking hold and thereby avoiding exacerbations of thedisorder, for example COPD, cystic fibrosis, bronchiectasis, asthma orcongestive heart failure. It will be appreciated that ‘prevention’ isnot an absolute term. In medicine, ‘prevention’ is understood to referto the prophylactic administration of a drug to substantially diminishthe likelihood or severity of a disorder or to delay the onset of such adisorder. Prophylactic administration may be particularly advisable whenthere is a heightened risk of infection, for example, in the case of HRVduring the winter months.

According to a further aspect the invention provides a method ofpreventing a viral infection comprising administering a compound offormula (I), or a pharmaceutically acceptable salt thereof, to a patientin need thereof.

According to a further aspect the invention provides a method ofpreventing a disorder caused or exacerbated by a viral infectioncomprising administering a compound of formula (I), or apharmaceutically acceptable salt thereof, to a patient in need thereof.In an embodiment, the disorder is COPD, cystic fibrosis, bronchiectasis,asthma or congestive heart failure. In a further embodiment, thedisorder is COPD or asthma. In a still further embodiment, the disorderis COPD.

According to a further aspect the invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof forpreventing a viral infection.

According to a further aspect the invention provides a compound offormula (I), or a pharmaceutically acceptable salt thereof forpreventing a disorder caused or exacerbated by a viral infection. In anembodiment, the disorder is COPD, cystic fibrosis, bronchiectasis,asthma or congestive heart failure. In a further embodiment, thedisorder is COPD or asthma. In a still further embodiment, the disorderis COPD.

According to a further aspect the invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for preventing a viral infection.

According to a further aspect the invention provides the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,in the manufacture of a medicament for preventing a disorder caused orexacerbated by a viral infection. In an embodiment, the disorder isCOPD, cystic fibrosis, bronchiectasis, asthma or congestive heartfailure. In a further embodiment, the disorder is COPD or asthma. In astill further embodiment, the disorder is COPD.

In addition the compounds of the invention may be prophylacticallyadministered to healthy humans if they are to be exposed to a heightenedrisk of viral infection, for example during a SARS outbreak or in anursing or care home environment when several residents have contractedan HRV infection. Therefore according to a further aspect the inventionprovides a method of preventing a viral infection comprisingadministering a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, to a human in need thereof.

The following embodiments apply to each of the above aspects relating tomedical use. In an embodiment the virus is a single stranded RNA virus.In a further embodiment the virus is a positive-sense, single-strandedRNA virus. In an embodiment the viral infection is human rhinovirus(HRV). In a further embodiment the viral infection is HRV wherein thedisorder caused by the virus is the common cold. In a further embodimentthe viral infection is HRV wherein the disorder caused by the virus isbronchiolitis, pneumonia, otitis media, sinusitis or acute bronchitis.In a further embodiment the secondary bacterial infection causespneumonia. In a further embodiment, disorders exacerbated by the virusare COPD, cystic fibrosis, bronchiectasis, asthma or congestive heartfailure. In a further embodiment the HRV is HRV-A. In a furtherembodiment the HRV is HRV-B. In a further embodiment the HRV is HRV-C.In a further embodiment, the compound of formula (I) is administered atthe onset of nasal symptoms of HRV to prevent lung-HRV infection,thereby reducing the frequency and severity of asthma exacerbations. Ina further embodiment, the compound of formula (I) is administered at theonset of nasal symptoms of HRV to prevent lung-HRV infection, therebyreducing the frequency and severity of COPD exacerbations. In a furtherembodiment, the compound of formula (I) is administered at the onset ofnasal symptoms of HRV to prevent lung-HRV infection, thereby reducingthe frequency and severity of cystic fibrosis exacerbations. In afurther embodiment, the compound of formula (I) is administered at theonset of nasal symptoms of HRV to prevent lung-HRV infection, therebyreducing the frequency and severity of congestive heart failureexacerbations.

In an embodiment the viral infection is coronavirus wherein the diseaseor condition is severe acute respiratory syndrome (SARS).

Formulations

The compounds of the invention will normally, but not necessarily, beformulated into pharmaceutical formulations prior to administration to apatient. According to a further aspect the invention provides apharmaceutical formulation comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient. According to a further aspect the inventionprovides a pharmaceutical formulation for treating a viral infectioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof. According to a further aspect the invention provides apharmaceutical formulation for treating a disorder caused or exacerbatedby a viral infection comprising a compound of formula (I) or apharmaceutically acceptable salt thereof. According to a further aspectthe invention provides a pharmaceutical formulation for treating asecondary bacterial infection caused by a viral infection, comprising acompound of formula (I) or a pharmaceutically acceptable salt thereof.According to a further aspect the invention provides a pharmaceuticalformulation for preventing a viral infection comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof. According toa further aspect the invention provides a pharmaceutical formulation forpreventing a disorder caused or exacerbated by a viral infectioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof.

As used herein, ‘pharmaceutically acceptable excipient’ means apharmaceutically acceptable material, composition or vehicle involved ingiving form or consistency to the pharmaceutical formulation. Eachexcipient must be compatible with the other ingredients of thepharmaceutical formulation when commingled such that interactions whichwould substantially reduce the efficacy of the compound of the inventionwhen administered to a patient and interactions which would result inpharmaceutical formulations that are not pharmaceutically acceptable areavoided. In addition, each excipient must of course be pharmaceuticallyacceptable e.g. of sufficiently high purity.

It is envisaged that the compounds of the invention may be administeredtopically, for example by inhalation, intranasally, transdermally,intraocularly or aurally.

According to a further aspect the invention is directed to a dosage formadapted for administration to a patient by inhalation, for example, as adry powder, an aerosol, a suspension or a solution formulation.

Dry powder formulations for delivery to the lung by inhalation typicallycomprise a compound of the invention as a finely divided powder togetherwith one or more pharmaceutically-acceptable excipients as finelydivided powders. Pharmaceutically-acceptable excipients particularlysuited for use in dry powders are known to those skilled in the art andinclude lactose, starch, mannitol, and mono-, di-, and polysaccharides.The finely divided powder may be prepared by, for example, micronisationand milling. Generally, the size-reduced (eg micronised) compound can bedefined by a D₅₀ value of about 1 to about 10 microns (for example asmeasured using laser diffraction).

The dry powder may be administered to the patient via a reservoir drypowder inhaler (RDPI) having a reservoir suitable for storing multiple(un-metered doses) of medicament in dry powder form. RDPIs typicallyinclude a means for metering each medicament dose from the reservoir toa delivery position. For example, the metering means may comprise ametering cup, which is movable from a first position where the cup maybe filled with medicament from the reservoir to a second position wherethe metered medicament dose is made available to the patient forinhalation.

The dry powder formulations for use in accordance with the presentinvention may be administered via inhalation devices. As an example,such devices can encompass capsules and cartridges of for examplegelatin, or blisters of, for example, laminated aluminum foil. Invarious embodiments, each capsule, cartridge or blister may containdoses of formulation according to the teachings presented herein.Examples of inhalation devices may include those intended for unit doseor multi-dose delivery of formulation, including all of the devices setforth herein. As an example, in the case of multi-dose delivery, theformulation can be pre-metered (e.g., as in DISKUS, see GB2242134, U.S.Pat. Nos. 6,032,666, 5,860,419, 5,873,360, 5,590,645, 6,378,519 and6,536,427 or Diskhaler, see GB 2178965, 2129691 and 2169265, U.S. Pat.Nos. 4,778,054, 4,811,731, 5,035,237) or metered in use (e.g. as inTurbuhaler, see EP 69715, or in the devices described in U.S. Pat. No.6,321,747). An example of a unit-dose device is ROTAHALER (see GB2064336). In one embodiment, the DISKUS inhalation device comprises anelongate strip formed from a base sheet having a plurality of recessesspaced along its length and a lid sheet peelably sealed thereto todefine a plurality of containers, each container having therein aninhalable formulation containing the compound optionally with otherexcipients and additive taught herein. The peelable seal is anengineered seal, and in one embodiment the engineered seal is a hermeticseal. Preferably, the strip is sufficiently flexible to be wound into aroll. The lid sheet and base sheet will preferably have leading endportions which are not sealed to one another and at least one of theleading end portions is constructed to be attached to a winding means.Also, preferably the engineered seal between the base and lid sheetsextends over their whole width. The lid sheet may preferably be peeledfrom the base sheet in a longitudinal direction from a first end of thebase sheet.

A dry powder formulation may also be presented in an inhalation devicewhich permits separate containment of two different components of theformulation, Thus, for example, these components are administrablesimultaneously but are stored separately, e.g. in separatepharmaceutical formulations, for example as described in WO 03/061743 A1WO 2007/012871 A1, WO2007/068896, as well as U.S. Pat. Nos. 8,113,199,8,161,968, 8,511,304, 8,534,281, 8,746,242 and 9,333,310.

In one embodiment an inhalation device permitting separate containmentof components is an inhaler device having two peelable blister strips,each strip containing pre-metered doses in blister pockets arrangedalong its length, e.g., multiple containers within each blister strip,e.g., ELLIPTA. Said device has an internal indexing mechanism which,each time the device is actuated, peels opens a pocket of each strip andpositions the blisters so that each newly exposed dose of each strip isadjacent to the manifold which communicates with the mouthpiece of thedevice. When the patient inhales at the mouthpiece, each dose issimultaneously drawn out of its associated pocket into the manifold andentrained via the mouthpiece into the patient's respiratory tract. Afurther device that permits separate containment of different componentsis DUOHALER of Innovata. In addition, various structures of inhalationdevices provide for the sequential or separate delivery of thepharmaceutical formulation(s) from the device, in addition tosimultaneous delivery.

Alternatively, the dry powder may be presented in capsules (e.g. gelatinor plastic), cartridges, or blister packs for use in a multi-dose drypowder inhaler (MDPI). MDPIs are inhalers wherein the medicament iscomprised within a multi-dose pack containing (or otherwise carrying)multiple defined doses (or parts thereof) of medicament. When the drypowder is presented as a blister pack, it comprises multiple blistersfor containment of the medicament in dry powder form. The blisters aretypically arranged in regular fashion for ease of release of themedicament therefrom. For example, the blisters may be arranged in agenerally circular fashion on a disc-form blister pack, or the blistersmay be elongate in form, for example comprising a strip or a tape. Eachcapsule, cartridge, or blister may, for example, contain between 200μg-10 mg of the compound of formula (I) or a pharmaceutically acceptablesalt thereof.

Aerosols may be formed by suspending or dissolving a compound of theinvention in a liquified propellant. Suitable propellants includehalocarbons, hydrocarbons, and other liquified gases. Representativepropellants include: trichlorofluoromethane (propellant 11),dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane(propellant 114), tetrafluoroethane (HFA-134a), 1,1-difluoroethane(HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12),heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane,perfluoropentane, butane, isobutane, and pentane. Aerosols comprising acompound of the invention will typically be administered to a patientvia a metered dose inhaler (MDI). Such devices are known to thoseskilled in the art.

The aerosol may contain additional pharmaceutically-acceptableexcipients typically used with MDIs such as surfactants, lubricants,cosolvents and other excipients to improve the physical stability of theformulation, to improve valve performance, to improve solubility, or toimprove taste.

According to a further aspect there is provided a pharmaceutical aerosolformulation comprising a compound of formula (I) or pharmaceuticallyacceptable salt thereof and a fluorocarbon or hydrogen-containingchlorofluorocarbon as propellant, optionally in combination with asurfactant and/or a cosolvent.

According to an embodiment, the propellant is selected from1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane andmixtures thereof.

The formulations of the invention may be buffered by the addition ofsuitable buffering agents.

Capsules and cartridges for use in an inhaler or insufflator, of forexample gelatine, may be formulated containing a powder mix forinhalation of a compound of the invention and a suitable powder basesuch as lactose or starch. Each capsule or cartridge may generallycontain from 200 μg to 10 mg of the compound of the invention.Alternatively, the compound of the invention may be presented withoutexcipients such as lactose.

The proportion of the compound of the invention in the localformulations according to the invention depends on the precise type offormulation to be prepared but will generally be within the range offrom 0.01 to 10% by weight. Generally, for most types of preparations,the proportion used will be within the range of from 0.05 to 1%, forexample from 0.1 to 0.5%.

Aerosol formulations are preferably arranged so that each metered doseor ‘puff’ of aerosol contains from 20 μg to 10 mg, preferably from 20 gto 5 mg, more preferably from about 20 μg to 0.5 mg of a compound of theinvention. Administration may be once daily or several times daily, forexample 2, 3, 4 or 8 times, giving for example 1, 2 or 3 doses eachtime. The overall daily dose with an aerosol will be within the rangefrom 20 μg to 2.0 mg, for example from 50 μg to 1.0 mg. The overalldaily dose and the metered dose delivered by capsules and cartridges inan inhaler or insufflator will generally be double that delivered withaerosol formulations.

In the case of suspension aerosol formulations, the particle size of theparticulate (e.g., micronised) drug should be such as to permitinhalation of substantially all the drug into the lungs uponadministration of the aerosol formulation and will thus be less than 100microns, desirably less than 20 microns, and in particular in the rangeof from 1 to 10 microns, such as from 1 to 5 microns, more preferablyfrom 2 to 3 microns.

The formulations of the invention may be prepared by dispersal ordissolution of the medicament and a compound of the invention in theselected propellant in an appropriate container, for example, with theaid of sonication or a high-shear mixer. The process is desirablycarried out under controlled humidity conditions.

The chemical and physical stability and the pharmaceutical acceptabilityof the aerosol formulations according to the invention may be determinedby techniques well known to those skilled in the art. Thus, for example,the chemical stability of the components may be determined by HPLCassay, for example, after prolonged storage of the product. Physicalstability data may be gained from other conventional analyticaltechniques such as, for example, by leak testing, by valve deliveryassay (average shot weights per actuation), by dose reproducibilityassay (active ingredient per actuation) and spray distribution analysis.

The stability of the suspension aerosol formulations according to theinvention may be measured by conventional techniques, for example, bymeasuring flocculation size distribution using a back light scatteringinstrument or by measuring particle size distribution by cascadeimpaction or by the ‘twin impinger’ analytical process. As used hereinreference to the ‘twin impinger’ assay means ‘Determination of thedeposition of the emitted dose in pressurised inhalations usingapparatus A’ as defined in British Pharmacopaeia 1988, pages A204-207,Appendix XVII C. Such techniques enable the ‘respirable fraction’ of theaerosol formulations to be calculated. One method used to calculate the‘respirable fraction’ is by reference to ‘fine particle fraction’ whichis the amount of active ingredient collected in the lower impingementchamber per actuation expressed as a percentage of the total amount ofactive ingredient delivered per actuation using the twin impinger methoddescribed above.

The term ‘metered dose inhaler’ or MDI means a unit comprising a can, asecured cap covering the can and a formulation metering valve situatedin the cap. MDI system includes a suitable channeling device. Suitablechanneling devices comprise for example, a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient such as a mouthpiece actuator.

MDI canisters generally comprise a container capable of withstanding thevapour pressure of the propellant used such as a plastic orplastic-coated glass bottle or preferably a metal can, for example,aluminium or an alloy thereof which may optionally be anodised,lacquer-coated and/or plastic-coated (for example incorporated herein byreference WO 96/32099 wherein part or all of the internal surfaces arecoated with one or more fluorocarbon polymers optionally in combinationwith one or more non-fluorocarbon polymers), which container is closedwith a metering valve. The cap may be secured onto the can viaultrasonic welding, screw fitting or crimping. MDIs taught herein may beprepared by methods of the art (e.g. see Byron, above and WO 96/32099).Preferably the canister is fitted with a cap assembly, wherein adrug-metering valve is situated in the cap, and said cap is crimped inplace.

In one embodiment of the invention the metallic internal surface of thecan is coated with a fluoropolymer, more preferably blended with anon-fluoropolymer. In another embodiment of the invention the metallicinternal surface of the can is coated with a polymer blend ofpolytetrafluoroethylene (PTFE) and polyethersulfone (PES). In a furtherembodiment of the invention the whole of the metallic internal surfaceof the can is coated with a polymer blend of polytetrafluoroethylene(PTFE) and polyethersulfone (PES).

The metering valves are designed to deliver a metered amount of theformulation per actuation and incorporate a gasket to prevent leakage ofpropellant through the valve. The gasket may comprise any suitableelastomeric material such as, for example, low density polyethylene,chlorobutyl, bromobutyl, EPDM, black and white butadiene-acrylonitrilerubbers, butyl rubber and neoprene. Suitable valves are commerciallyavailable from manufacturers well known in the aerosol industry, forexample, from Valois, France (e.g. DF10, DF30, DF60), Bespak plc, UK(e.g. BK300, BK357) and 3M-Neotechnic Ltd, UK (e.g. SPRAYMISER).

In various embodiments, the MDIs may also be used in conjunction withother structures such as, without limitation, overwrap packages forstoring and containing the MDIs, including those described in U.S. Pat.Nos. 6,119,853; 6,179,118; 6,315,112; 6,352,152; 6,390,291; and6,679,374, as well as dose counter units such as, but not limited to,those described in U.S. Pat. Nos. 6,360,739 and 6,431,168.

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large-scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method for preparing suspension aerosol formulations ametering valve is crimped onto an aluminium can to form an emptycanister. The particulate medicament is added to a charge vessel andliquefied propellant together with the optional excipients is pressurefilled through the charge vessel into a manufacturing vessel. The drugsuspension is mixed before recirculation to a filling machine and analiquot of the drug suspension is then filled through the metering valveinto the canister. In one example bulk manufacturing method forpreparing solution aerosol formulations a metering valve is crimped ontoan aluminium can to form an empty canister. The liquefied propellanttogether with the optional excipients and the dissolved medicament ispressure filled through the charge vessel into a manufacturing vessel.

In an alternative process, an aliquot of the liquefied formulation isadded to an open canister under conditions which are sufficiently coldto ensure the formulation does not vaporise, and then a metering valvecrimped onto the canister.

Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing. Suspensions and solutionscomprising a compound of the invention may also be administered to apatient via a nebuliser. The solvent or suspension agent utilized fornebulization may be any pharmaceutically-acceptable liquid such aswater, aqueous saline, alcohols or glycols, e.g., ethanol,isopropylalcohol, glycerol, propylene glycol, polyethylene glycol, etc.or mixtures thereof. Saline solutions utilize salts which display littleor no pharmacological activity after administration. Both organic salts,such as alkali metal or ammonium halogen salts, e.g., sodium chloride,potassium chloride or organic salts, such as potassium, sodium andammonium salts or organic acids, e.g., ascorbic acid, citric acid,acetic acid, tartaric acid, etc. may be used for this purpose.

Other pharmaceutically-acceptable excipients may be added to thesuspension or solution. The compound of the invention may be stabilizedby the addition of an inorganic acid, e.g., hydrochloric acid, nitricacid, sulfuric acid and/or phosphoric acid; an organic acid, e.g.,ascorbic acid, citric acid, acetic acid, and tartaric acid, etc., acomplexing agent such as EDTA or citric acid and salts thereof; or anantioxidant such as antioxidant such as vitamin E or ascorbic acid.These may be used alone or together to stabilize the compound of formula(I) or pharmaceutically acceptable salt thereof. Preservatives may beadded such as benzalkonium chloride or benzoic acid and salts thereof.Surfactant may be added particularly to improve the physical stabilityof suspensions. These include lecithin, disodium dioctylsulfosuccinate,oleic acid and sorbitan esters.

Formulations for administration to the nose may include pressurisedaerosol formulations and aqueous formulations administered to the noseby pressurised pump.

Formulations which are non-pressurised and adapted to be administeredtopically to the nasal cavity are of particular interest. Suitableformulations contain water as the diluent or carrier for this purpose.Aqueous formulations for administration to the lung or nose may beprovided with conventional excipients such as buffering agents, tonicitymodifying agents and the like. Aqueous formulations may also beadministered to the nose by nebulisation.

The compounds of the invention may be formulated as a fluid formulationfor delivery from a fluid dispenser, for example a fluid dispenserhaving a dispensing nozzle or dispensing orifice through which a metereddose of the fluid formulation is dispensed upon the application of auser-applied force to a pump mechanism of the fluid dispenser. Suchfluid dispensers are generally provided with a reservoir of multiplemetered doses of the fluid formulation, the doses being dispensable uponsequential pump actuations. The dispensing nozzle or orifice may beconfigured for insertion into the nostrils of the user for spraydispensing of the fluid formulation into the nasal cavity. A fluiddispenser of the aforementioned type is described and illustrated in WO05/044354, the entire content of which is hereby incorporated herein byreference. The dispenser has a housing which houses a fluid dischargedevice having a compression pump mounted on a container for containing afluid formulation. The housing has at least one finger-operable sidelever which is movable inwardly with respect to the housing to cam thecontainer upwardly in the housing to cause the pump to compress and pumpa metered dose of the formulation out of a pump stem through a nasalnozzle of the housing. In one embodiment, the fluid dispenser is of thegeneral type illustrated in FIGS. 30-40 of WO 05/044354.

Pharmaceutical formulations adapted for intranasal administrationwherein the carrier is a solid include a coarse powder having a particlesize for example in the range 20 to 500 microns which is administered byrapid inhalation through the nasal passage from a container of thepowder held close up to the nose. Suitable formulations wherein thecarrier is a liquid, for administration as a nasal spray or as nasaldrops, include aqueous or oil solutions of the compound of theinvention.

Some of the disorders caused or exacerbated by viral infections myresult in skin problems, for example skin rashes. Pharmaceuticalformulations adapted for transdermal administration may be presented asdiscrete patches intended to remain in intimate contact with theepidermis of the patient for a prolonged period of time. For example,the active ingredient may be delivered from the patch by iontophoresisas generally described in Pharmaceutical Research, 3(6), 318 (1986).

Pharmaceutical formulations adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

Ointments, creams and gels, may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agent and/or solvents. Such bases may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a solvent such as polyethylene glycol.Thickening agents and gelling agents which may be used according to thenature of the base include soft paraffin, aluminium stearate,cetostearyl alcohol, polyethylene glycols, woolfat, beeswax,carboxypolymethylene and cellulose derivatives, and/or glycerylmonostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or non-aqueous base also comprising one ormore dispersing agents, solubilising agents, suspending agents orpreservatives.

Topical preparations may be administered by one or more applications perday to the affected area. Over skin areas, occlusive dressings mayadvantageously be used. Continuous or prolonged delivery may be achievedby an adhesive reservoir system.

For intraocular or aural treatment formulations may be applied as atopical ointment or cream. When formulated in an ointment, the compoundof formula (I) or a pharmaceutically acceptable salt thereof may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the compound of formula (I) or pharmaceuticallyacceptable salt thereof may be formulated in a cream with anoil-in-water cream base or a water-in-oil base.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions which maycontain anti-oxidants, buffers, bacteriostats and solutes which renderthe formulation isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The formulations may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

Compounds or pharmaceutical formulations of the invention may beadministered together with an anti-inflammatory agent such as acorticosteroid or a pharmaceutical formulation thereof, for thetreatment of asthma exacerbated by viral infections, particularly HRVinfections. For example, compounds of the invention may be formulatedtogether with an anti-inflammatory agent, such as a corticosteroid, in asingle formulation, such as a dry powder formulation for inhalation.Alternatively, a pharmaceutical formulation comprising a compound of theinvention may be administered in conjunction with a pharmaceuticalformulation comprising an anti-inflammatory agent, such as acorticosteroid, either simultaneously or sequentially. For example, apharmaceutical formulation comprising a compound of the invention and afurther pharmaceutical formulation comprising an anti-inflammatoryagent, such as a corticosteroid, may each be held in device suitable forthe simultaneous administration of both formulations via inhalation.

Suitable corticosteroids for administration together with compounds ofthe invention include fluticasone furoate, fluticasone propionate,beclomethasone diproprionate, budesonide, ciclesonide, mometasonefuroate, triamcinolone, flunisolide and prednisilone. Suitablecorticosteroids for administration together with compounds of theinvention via inhalation include fluticasone furoate, fluticasonepropionate, beclomethasone diproprionate, budesonide, ciclesonide,mometasone furoate, and flunisolide.

Therefore according to a further aspect, the invention provides apharmaceutical formulation comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and one or moreanti-inflammatory agents, such as a corticosteroid or an inhibitor ofphosphatidylinositol-4,5-bisphosphate 3-kinase-delta (PI3Kδ).

According to a further aspect, the invention provides a method oftreatment of asthma exacerbated by a viral infection, for example HRV,which method comprises administering to a subject in need thereof atherapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof and one or moreanti-inflammatory agents, such as a corticosteroid.

According to a further aspect, the invention provides a compound offormula (I) or a pharmaceutically acceptable salt thereof and one ormore anti-inflammatory agents, such as a corticosteroid, for use in thetreatment of asthma exacerbated by viral infection.

According to a further aspect, the invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereofand one or more anti-inflammatory agents, such as a corticosteroid, inthe manufacture of a medicament for the treatment of asthma exacerbatedby viral infection.

According to a further aspect, the invention provides a method oftreatment of cystic fibrosis exacerbated by a viral infection, forexample HRV, which method comprises administering to a subject in needthereof a therapeutically effective amount of a compound of formula (I)or a pharmaceutically acceptable salt thereof and one or moreanti-inflammatory agents, such as a corticosteroid.

According to a further aspect, the invention provides a compound offormula (I) or a pharmaceutically acceptable salt thereof and one ormore anti-inflammatory agents, such as a corticosteroid, for use in thetreatment of cystic fibrosis exacerbated by viral infection.

According to a further aspect, the invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereofand one or more anti-inflammatory agents, such as a corticosteroid, inthe manufacture of a medicament for the treatment of cystic fibrosisexacerbated by viral infection.

According to a further aspect, the invention provides a method oftreatment of congestive heart failure exacerbated by a viral infection,for example HRV, which method comprises administering to a subject inneed thereof a therapeutically effective amount of a compound of formula(I) or a pharmaceutically acceptable salt thereof and one or moreanti-inflammatory agents, such as a corticosteroid.

According to a further aspect, the invention provides a compound offormula (I) or a pharmaceutically acceptable salt thereof and one ormore anti-inflammatory agents, such as a corticosteroid, for use in thetreatment of congestive heart failure exacerbated by viral infection.

According to a further aspect, the invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereofand one or more anti-inflammatory agents, such as a corticosteroid, inthe manufacture of a medicament for the treatment of congestive heartfailure exacerbated by viral infection.

The following embodiments apply to each of the above aspects relating tocombinations with one or more anti-inflammatory agents.

In an embodiment the pharmaceutical formulation comprises oneanti-inflammatory agent.

In one embodiment the anti-inflammatory agent is a corticosteroid.

In one embodiment the corticosteroid is fluticasone furoate.

In one embodiment the corticosteroid is fluticasone propionate.

In one embodiment the anti-inflammatory agent is an inhibitor ofphosphatidylinositol-4,5-bisphosphate 3-kinase-delta (PI3Kδ), such asnemiralisib (see Sriskantharajah et al., Annals of the New York Academyof Sciences, (2013), 1280, 35; Cahn et al., Pulmonary Pharmacology andTherapeutics, (2017), 46, 69; and Stark et al., Current Opinion inPharmacology, (2015), 23, 82).

Compounds or pharmaceutical formulations of the invention may beadministered together with one or more bronchodilators, orpharmaceutical formulations thereof, for the treatment of COPDexacerbated by viral infection. For example, compounds of the inventionmay be formulated together with one or more bronchodilators in a singleformulation, such as a dry powder formulation for inhalation.Alternatively, a pharmaceutical formulation comprising a compound of theinvention may be administered in conjunction with a pharmaceuticalformulation comprising one or more bronchodilators, eithersimultaneously or sequentially. In a further alternative, a formulationcomprising a compound of the invention and a bronchodilator may beadministered in conjunction with a pharmaceutical formulation comprisinga further bronchodilator. For example, a pharmaceutical formulationcomprising a compound of the invention and a further pharmaceuticalformulation comprising one or more bronchodilators may each be held indevice suitable for the simultaneous administration of both formulationsvia inhalation.

Suitable bronchodilators for administration together with compounds ofthe invention include β₂-adrenoreceptor agonists and anticholinergicagents. Examples of β₂-adrenoreceptor agonists, include, for example,vilanterol, salmeterol, salbutamol, formoterol, salmefamol, fenoterolcarmoterol, etanterol, naminterol, clenbuterol, pirbuterol, flerbuterol,reproterol, bambuterol, indacaterol, terbutaline and salts thereof, forexample the xinafoate (1-hydroxy-2-naphthalenecarboxylate) salt ofsalmeterol, the sulphate salt of salbutamol or the fumarate salt offormoterol. Examples of anticholinergic agents include umeclidinium (forexample as the bromide), ipratropium (for example, as the bromide),oxitropium (for example, as the bromide) and tiotropium (for example, asthe bromide). In one embodiment, a compound of the invention may beadministered together with a β₂-adrenoreceptor agonist, such asvilanterol, and an anticholinergic agent, such as, umeclidinium.

According to a further aspect the invention provides a pharmaceuticalformulation comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and one or more bronchodilators.

According to a further aspect the invention provides a method oftreatment of COPD exacerbated by a viral infection which methodcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and one or more bronchodilators.

According to a further aspect, the invention provides a compound offormula (I) or a pharmaceutically acceptable salt thereof and one ormore bronchodilators for use in the treatment of COPD exacerbated byviral infection.

According to a further aspect, the invention provides the use of acompound of formula (I) or a pharmaceutically acceptable salt thereofand one or more bronchodilators, in the manufacture of a medicament forthe treatment of COPD exacerbated by a viral infection.

The following embodiments apply to each of the above aspects relating tocombinations with one or more bronchodilators.

In an embodiment the one or more bronchodilators comprise one or moreβ₂-adrenoreceptor agonists.

In an embodiment the one or more bronchodilators comprise one or moreanticholinergic agents.

In an embodiment the one or more bronchodilators comprise one or moreβ₂-adrenoreceptor agonists and one or more anticholinergic agents.

In an embodiment the one or more bronchodilators comprise aβ₂-adrenoreceptor agonist and an anticholinergic agent.

In an embodiment the one or more bronchodilators comprise onebronchodilator which is a β₂-adrenoreceptor agonist.

In an embodiment the one or more bronchodilators comprise onebronchodilator which is an anticholinergic agent.

In an embodiment, the β₂-adrenoreceptor agonist is vilanterol.

In an embodiment, the anticholinergic agent is umeclidinium. In afurther embodiment, the anticholinergic agent is umeclidinium bromide.

According to a further aspect the invention provides a pharmaceuticalformulation comprising a) a compound of formula (I) or apharmaceutically acceptable salt thereof, b) one or morebronchodilators, and c) one or more anti-inflammatory agent.

According to a further aspect the invention provides a method oftreatment of COPD exacerbated by a viral infection which methodcomprises administering to a subject in need thereof a therapeuticallyeffective amount of a) a compound of formula (I) or a pharmaceuticallyacceptable salt thereof, b) one or more bronchodilators, and c) one ormore anti-inflammatory agent.

According to a further aspect, the invention provides a) a compound offormula (I) or a pharmaceutically acceptable salt thereof, b) one ormore bronchodilators, and c) one or more anti-inflammatory agent for usein the treatment of COPD exacerbated by viral infection.

According to a further aspect, the invention provides the use of a) acompound of formula (I) or a pharmaceutically acceptable salt thereof,b) one or more bronchodilators, and c) one or more anti-inflammatoryagent in the manufacture of a medicament for the treatment of COPDexacerbated by a viral infection.

The following embodiments apply to each of the above aspects relating tocombinations with one or more bronchodilators and one or moreanti-inflammatory agents.

In an embodiment the one or more bronchodilators comprise one or moreβ₂-adrenoreceptor agonists.

In an embodiment the one or more bronchodilators comprise one or moreanticholinergic agents.

In an embodiment the one or more bronchodilators comprise one or moreβ₂-adrenoreceptor agonists and one or more anticholinergic agents.

In an embodiment the one or more bronchodilators comprise aβ₂-adrenoreceptor agonist and an anticholinergic agent.

In an embodiment the one or more bronchodilators comprise onebronchodilator which is a β₂-adrenoreceptor agonist.

In an embodiment the one or more bronchodilators comprise onebronchodilator which is an anticholinergic agent.

In an embodiment, the β₂-adrenoreceptor agonist is vilanterol.

In an embodiment, the anticholinergic agent is umeclidinium. In afurther embodiment, the anticholinergic agent is umeclidinium bromide.

In an embodiment the one or more anti-inflammatory agent is acorticosteroid.

In a further embodiment the corticosteroid is fluticasone furoate.

In a further embodiment the corticosteroid is fluticasone propionate.

In a further embodiment the one or more bronchodilators are vilanteroland umeclidinium.

In a further embodiment the one or more bronchodilators are bothvilanterol and umeclidinium, and the one or more anti-inflammatoryagents is fluticasone furoate.

In a further embodiment the one or more bronchodilators are bothvilanterol and umeclidinium, and the one or more anti-inflammatoryagents is fluticasone propionate.

The compounds of the invention may possess an improved profile overknown PI4KIIIβ inhibitors, for example, compared to known PI4KIIIβinhibitors certain compounds of the invention may have one or more ofthe following properties:

(i) more potent PI4KIIIβ inhibitory activity;

(ii) improved selectivity for PI4KIIIβ;

(iii) increased enzyme T_(1/2);

(iv) improved cell potency;

(v) Improved lung retention

(vi) improved solubility; and/or

(vii) lower levels of compound accumulating in body tissue.

As stated above, when administered, lower levels of compounds of thepresent invention may accumulate in body tissue compared to knownPI4KIIIβ inhibitors. In particular, compounds of the invention may havelower accumulation levels in the spleen. Previous studies have shownthat accumulation of PI4KIIIβ inhibitors in the spleen may bedisadvantageous e.g. may cause apoptosis.

Supporting Compounds

The following supporting compounds illustrate the invention, as guidanceto the skilled artisan to prepare and use the compounds, formulations,and methods of the invention. While particular embodiments of theinvention are described, the skilled artisan will appreciate thatvarious changes and modifications can be made. References topreparations carried out in a similar manner to, or by the generalmethod of, other preparations, may encompass variations in routineparameters such as time, temperature, workup conditions, changes inreagent amounts etc.

Reactions involving metal hydrides (including sodium hydride) andorgano-metallic reagents are carried out under argon or nitrogen unlessotherwise specified.

In the following Intermediates and Supporting Compounds, where therelative stereochemistry of the compound has been identified, this isindicated both in the name and structure of the compound.

In certain of the following Intermediates and Supporting compounds,starting materials are identified by reference to other Intermediate orCompound numbers. This does not signify that the actual material (or“batch”) obtained from any particular Intermediate or SupportingCompound was necessarily used in a subsequent step exemplified herein.

Unless stated otherwise, starting materials were commercially available.All solvents and commercial reagents were of laboratory grade and wereused as received.

Where the absolute stereochemistry is known and the compound is a singleenantiomer, the bold or hashed wedges symbols (

) are used as appropriate. Where the absolute stereochemistry is unknownbut is known to be a single enantiomer, a star (*) is used.

The names of the intermediates and Supporting Compounds have beenobtained using the compound naming program within “ChemBioDraw Ultrav12” or “ACD Name Pro 6.02”.

As used herein the symbols and conventions used in these processes,schemes and examples are consistent with those used in the contemporaryscientific literature, for example, the Journal of the American ChemicalSociety.

Abbreviations

The following list provides definitions of certain abbreviations andsymbols as used herein. It will be appreciated that the list is notexhaustive, but the meaning of those abbreviations and symbols notherein below defined will be readily apparent to those skilled in theart. In describing the invention, chemical elements are identified inaccordance with the Periodic Table of the Elements.

-   Bu Butyl-   m-CPBA Meta-Chloroperoxybenzoic acid-   CV Column volume(s)-   DCM Dichloromethane-   DIBAL-H Diisobutylaluminium hydride-   DIPEA N,N-Diisopropylethylamine-   DMAP 4-Dimethylaminopyridine-   DMP Dess-Martin periodinane-   DMF N,N-Dimethylformamide-   DMSO Dimethylsulfoxide-   dppf 1,1′-Bis(diphenylphosphino)ferrocene-   HATU    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium    3-oxide hexafluorophosphate-   HCl Hydrochloric acid-   IPA Iso-propanol-   2-MeTHF 2-Methyltetrahydrofuran-   NBS N-Bromosuccinimde-   NIS N-Iodosuccinimde-   rt Retention time-   TFA Trifluoroacetic acid-   THE Tetrahydrofuran-   HPLC High performance liquid chromatography-   MDAP Mass Directed Autopreparative HPLC-   XPhos    Dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-3-yl)phosphane-   XPhos Pd G2    Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)

LCMS Methods

Method A

Column: Acquity BEH C₁₈ (50 mm×2.1 mm, 1.7 μm). Mobile phase: A: 0.1%formic acid in water; B: 0.1% formic acid in acetonitrile. Time (min)/%B: 0/3, 0.4/3, 2.0/98, 3.4/98, 3.5/3, 4.0/3. Column temp: 35° C., Flowrate: 0.6 mL/min.

Method B

Column: XBridge BEH C₁₈ (50 mm×4.6 mm, 2.5 μM). Mobile phase: A: 5 mMammonium bicarbonate; B: acetonitrile. Time (min)/% B: 0/5, 0.5/5, 1/15,3.3/98, 5.2/98, 5.5/5, 6.0/5. Column temp: 35° C., Flow rate: 1.3mL/min.

Method C

Column: Acquity BEH C₁₈ (50 mm×2.1 mm, 1.7 μm). Mobile phase: A: 0.1%formic acid in water; B: 0.1% formic acid in acetonitrile. Time (min)/%B: 0/3, 0.4/3, 2.5/98, 3.4/98, 3.5/3, 4.0/3. Column temp: 35° C., Flowrate: 0.6 mL/min.

Method D

Column: XBridge BEH C₁₈ (50 mm×4.6 mm, 2.5 μM). Mobile phase: A: 5 mMammonium bicarbonate; B: acetonitrile. Time (min)/% B: 0/5, 1.5/15,7/98, 9/98, 9.5/5, 10/5. Column temp: 35° C., Flow rate: 1.3 mL/min.

Method E

Column: Acquity BEH C₁₈ (50 mm×2.1 mm, 1.7 μm). Mobile phase: A: 0.05%formic acid in water; B: 0.05% formic acid in acetonitrile. Time (min)/%B: 0/3, 0.4/3, 3.2/98, 3.8/98, 4.2/3, 4.5/3. Column temp: 35° C., Flowrate: 0.6 mL/min.

Method F

Column: Acquity UPLC CSH C₁₈ column (50 mm×2.1 mm i.d. 1.7 μm) at 40° C.The solvents employed were: A=10 mM ammonium bicarbonate in wateradjusted to pH 10 with ammonia solution. B=Acetonitrile. Time (min)/% B:0/3, 0.05/3, 1.5/95, 1.9/95, 2.0/3. Flow rate: 1 mL/min. MS: Waters ZQ.Ionisation mode: Alternate-scan positive and negative electrospray

Method G

Column: Acquity BEH C₁₈ (50 mm×2.1 mm, 1.7 μm). Mobile phase: A: 0.1%formic acid in water; B: 0.1% formic acid in acetonitrile. Time (min)/%B: 0/3, 0.4/3, 3.2/98, 3.8/98, 4.2/3, 4.5/3. Column temp: 35° C., Flowrate: 0.6 mL/min.

Method H

Column: Acquity BEH C₁₈ (50 mm×2.1 mm, 1.7 μm). Mobile Phase: A: 5 mMAmmonium bicarbonate in water (pH 10); B: acetonitrile. Time (min)/% B:0/3, 0.4/3, 2.5/98, 3.4/98, 3.5/3, 4.0/3. Column temp: 35° C., FlowRate: 0.6 mL/min.

Method I

Column: Acquity BEH C₁₈ (100 mm×2.1 mm, 1.7 μm). Mobile phase: A: 0.05%TFA in water; B: acetonitrile. Time (min)/% B: 0/3, 0.4/3, 3.5/98,4.5/98, 5.0/3, 5.5/3. Column temp: 35° C., Flow Rate: 0.45 mL/min.

Method J

Column: Acquity UPLC CSH C₁₈ (50 mm×2.1 mm, i.d. 1.7 μm) at 40° C. Thesolvents employed were: A=0.1% v/v solution of formic acid in water.B=0.1% v/v solution of formic acid in acetonitrile. Time (min)/% B: 0/3,1.5/95, 1.9/95, 2.0/3. Flow rate: 1 mL/min. MS: Waters ZQ. Ionisationmode: Alternate-scan positive and negative electrospray

Method K

Column: XSelect CSH C₁₈ (150 mm×3.0 mm, 2.5 μm). Mobile phase: A: 0.05%TFA in water; B: 100% acetonitrile. Time (min)/% B: 0/3, 1/3, 8/98,11/98, 11.1/3, 12/3. Column temp.: 35° C., Flow Rate: 0.7 mL/min.

Method L

Column: BEH C₁₈ (100 mm×2.1 mm, 1.7 μm). Mobile Phase: A: 0.1% TFA inwater, B: 0.1% TFA in acetonitrile. Time (min)/% B: 0/3, 8.5/100,9.0/100, 9.5/3, 10/3. Column temp.: 50° C., Flow Rate: 0.55 mL/min.

Method M

Column: CSH C₁₈ (100 mm×2.1 mm i.d. 1.7 μm). Mobile phase: A: 0.1% v/vsolution of Formic Acid in Water; B: 0.1% v/v solution of Formic Acid inAcetonitrile. Time (min)/% B: 0/3, 8.5/99.9, 9/99.9, 9.5/3, 10/3. Columntemp.: 50° C. Flow rate: 0.8 mL/min.

Mass Directed Automated Preparative HPLC (MDAP)

The methods for the Mass Directed Automated Preparative HPLC used forthe purification of compounds are described below. Solvent elutiongradients range between 0 to 99% of Solvent B in Solvent A and run overa time period of up to 25 min.

For all Methods (unless specified):

The DAD detection was 210 nm to 350 nm. MS Conditions: MS: Waters ZQ

Ionisation mode: Alternate scan positive/negative Electrospray

Scan Range: 100 to 1000 AMU. Scan Time: 0.2 s or 0.50 s. Inter scanDelay: 0.1 s or 0.2 s Injection Volume: 1 mL or 3 mL

Method A

Column: Xselect CSH C₁₈ column (150 mm×30 mm i.d. 5 μm packing diameter)at ambient temp. The solvents employed were:

A=10 mM ammonium bicarbonate adjusted to pH 10 with ammonia in water.

B=acetonitrile.

Flow rate: 40 mL/min.

Method B

Column: Xselect CSH C₁₈ column (150 mm×30 mm i.d. 5 μm packing diameter)at ambient temp. The solvents employed were:

A=0.1% v/v solution of formic acid in water

B=0.1% v/v solution of formic acid in acetonitrile.

Flow rate: 40 mL/min.

Intermediate 1 2-Bromo-1-methyl-1H-imidazole

1-Methyl-1H-imidazole (20 g, 244 mmol) was dissolved in anhydrous THE(200 mL) under a nitrogen atmosphere. The solution was stirred at −78°C. and n-BuLi (167 mL, 268 mmol) was added dropwise slowly at −78° C.After 1 h, CBr₄ (97 g, 292 mmol) solution in anhydrous THE (200 mL) wasadded. The solution was stirred for 2 h at −78° C. and for 1 h at roomtemp. The reaction mixture was quenched with saturated aqueous ammoniumchloride (300 mL), extracted with ethyl acetate (2×200 mL), dried overanhydrous sodium sulphate, filtered and evaporated under reducedpressure. The crude compound was purified by silica gel chromatographyeluting with 60% ethyl acetate in pet. ether to afford the titlecompound. LCMS (method B): rt=1.89, [M+H]⁺=161.

Intermediate 2 3-(1-Methyl-1H-imidazol-2-yl)benzonitrile

A mixture of (3-cyanophenyl)boronic acid (16 g, 109 mmol),2-bromo-1-methyl-1H-imidazole (intermediate 1, 15.8 g, 98 mmol) andsodium carbonate (46.2 g, 436 mmol) in IPA (120 mL) and water (120 mL)was stirred and degassed with nitrogen for 20 min, and thenPdCl₂(dppf)-DCM adduct (4.45 g, 5.44 mmol) was added and stirred at 130°C. for 18 h in a sealed tube. After cooling, the reaction mixture wasdiluted with ethyl acetate (300 mL), washed with water (300 mL), driedover anhydrous sodium sulphate, filtered and evaporated under reducedpressure. The crude compound was purified by silica gel chromatographyeluting with 70% ethyl acetate in pet. ether to afford the titlecompound. LCMS (method C): rt=0.57, [M+H]⁺=184.

Intermediate 3 (3-(1-Methyl-1H-imidazol-2-yl)phenyl)methanamine

To a mixture of 3-(1-methyl-1H-imidazol-2-yl)benzonitrile (intermediate2, 12 g, 65.5 mmol) in 7 M ammonia in methanol (150 mL) was added Raneynickel (5 g, 65.5 mmol) at 0° C. The reaction mixture was stirred underhydrogen pressure (60 psi) at room temp. for 24 h. The reaction mixturewas filtered through a CELITE pad, washed with methanol (300 mL) and thefiltrate was concentrated under reduced pressure. The reaction wasrepeated on the same scale. The two batches of crude material werecombined and purified by neutral alumina chromatography to afford thetitle compound. LCMS (method D): rt=2.91, [M+H]⁺=188.

Intermediate 4 Ethyl7-hydroxy-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate

To a solution of sodium (Z)-1,4-diethoxy-1,4-dioxobut-2-en-2-olate(21.64 g, 103 mmol) in ethanol (100 mL) was added 4 M HCl in 1,4 dioxane(28.3 mL) followed by 5-methyl-1H-pyrazol-3-amine (10 g, 103 mmol) at 0°C. The reaction was heated to 85° C. and stirred for 3 h. The reactionmixture was cooled to room temp. and concentrated. The residue wasdissolved in 10% methanol in DCM (200 mL) and washed with saturatedsodium bicarbonate solution (100 mL). The organic layer was washed withbrine (50 mL), dried over anhydrous sodium sulphate, filtered andevaporated to dryness under reduced pressure. The residue was trituratedwith diethyl ether to give the title compound. LCMS (method A): rt=1.53,[M+H]⁺=222.

Intermediate 5 Ethyl7-chloro-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate

To ethyl 7-hydroxy-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 4, 10 g, 45.2 mmol) was added phosphorous oxychloride (50mL, 536 mmol) and the reaction was stirred for 24 h at 90° C. Thereaction mixture was cooled to room temp. and concentrated under reducedpressure. The residue was dissolved in DCM (100 mL) and the pH wasadjusted to neutral by using aqueous saturated sodium bicarbonatesolution (60 mL). The organic layer was washed with water (100 mL),brine (100 mL), dried over sodium sulphate, filtered and concentrated.The residue was dissolved in 10% methanol in DCM (100 mL), and adsorbedon silica (14 g) then purified by silica chromatography (50 g), elutingwith 10% ethyl acetate in pet. ether. Product fractions were combinedand evaporated under reduced pressure to give the title compound. LCMS(method B): rt=3.13, [M+H]⁺=240.

Intermediate 6 Ethyl7-chloro-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate

To a solution of ethyl7-chloro-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate (intermediate5, 15 g, 62.6 mmol) in DCM (220 mL) was added acetic acid (25 mL) andNIS (14.79 g, 65.7 mmol). The reaction was stirred for 6 h at 28° C. Thereaction mixture was diluted with DCM (150 mL), washed with saturatedsodium thiosulphate (2×90 mL), brine (60 mL), dried over sodiumsulphate, filtered and concentrated to give the title compound. LCMS(method A): rt=2.24, [M+H]⁺=366.

Intermediate 7 Ethyl3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate

To a solution of DIPEA (14.33 mL, 82 mmol) in DMSO (50 mL) was added(3-(1-methyl-1H-imidazol-2-yl)phenyl)methanamine (intermediate 3, 5.38g, 28.7 mmol) and ethyl7-chloro-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 6, 10 g, 27.4 mmol) and the reaction was stirred for 16 h.The reaction mixture was poured into ice cold water (200 mL) and a solidwas filtered, washed with water (50 mL) and dried under vacuum to givethe title compound. LCMS (method A): rt=1.79, [M+H]⁺=517.

Intermediate 8 4-Bromo-1-methoxy-2-(methylsulfonyl)benzene

To a stirred solution of sodium sulfite (16.55 g, 131 mmol) and sodiumbicarbonate (11.03 g, 131 mmol) in water (160 mL) was added5-bromo-2-methoxybenzene-1-sulfonyl chloride (25 g, 88 mmol) in1,4-dioxane (160 mL) at 70° C. The reaction mixture was stirred at 70°C. for 1 h. The reaction mixture was cooled to room temp. and thesolvent was removed under reduced pressure to afford the crudeintermediate as a white solid. The crude product was dissolved in DMF(300 mL) and methyl iodide (10.95 mL, 175 mmol) was added at room temp.and the mixture was stirred at room temp. for 2 h. The reaction mixturewas poured into ice-cooled water, extracted with ethyl acetate (300 mL),dried over anhydrous sodium sulphate, filtered and dried under reducedpressure. The crude compound was washed with n-pentane (100 mL) toafford the title compound. LCMS (method A): rt=1.84, [M+H]⁺=265.

Intermediate 92-(4-Methoxy-3-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

To a stirred solution of 4-bromo-1-methoxy-2-(methylsulfonyl)benzene(intermediate 8, 15 g, 56.6 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (21.55 g, 85mmol) in 1,4-dioxane (150 mL) was added potassium acetate (8.33 g, 85mmol) at room temp. The reaction mixture was degassed with argon for 15min then PdCl₂(dppf)-DCM adduct (2.31 g, 2.83 mmol) was added to thereaction mixture at room temp. and again degassed for 15 min under argonatmosphere. The reaction mixture was stirred at 100° C. for 3 h. Aftercooling, the reaction mixture was filtered through a CELITE pad, washedwith methanol (50 mL) and the filtrate was concentrated under reducedpressure. The crude product was purified by silica gel chromatographyeluting with 20% ethyl acetate in hexane to afford the title compound.LCMS (method E): rt=2.16, [M+H]⁺=313.

Intermediate 10 Ethyl3-(4-methoxy-3-(methylsulfonyl)phenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate

2-(4-Methoxy-3-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(intermediate 9, 680 mg, 2.179 mmol), ethyl3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 7, 750 mg, 1.453 mmol),chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(57.1 mg, 0.073 mmol) and potassium fluoride (253 mg, 4.36 mmol) weredissolved in 1,4-dioxane (10 mL) and water (5 mL) in a microwave vial,and the vial sealed and degassed with nitrogen. The reaction was stirredat 80° C. for 16 h. Furtherchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(57.1 mg, 0.073 mmol), potassium fluoride (253 mg, 4.36 mmol) and2-(4-methoxy-3-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(intermediate 9, 680 mg, 2.179 mmol) were added and the reaction stirredfor a further 8 h at 80° C. Furtherchloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(57.1 mg, 0.073 mmol), potassium fluoride (253 mg, 4.36 mmol) and2-(4-methoxy-3-(methylsulfonyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(intermediate 9, 680 mg, 2.179 mmol) were added and the reaction stirredfor a further 16 h at 80° C. The reaction was cooled to room temp.,filtered through CELITE (washing with 3×20 mL ethyl acetate) and thesolvent removed in vacuo. The reaction mixture was partitioned betweenethyl acetate (50 mL) and water (20 mL) and the organic phase separated,dried through a hydrophobic filter, and the solvent removed in vacuo.Purification by silica chromatography (120 g) eluting with 0-100% ethylacetate in cyclohexane over 20 CV gave title compound. LCMS (method F):rt=1.04, [M+H]⁺=515.

Intermediate 11(3-(4-Methoxy-3-(methylsulfonyl)phenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)methanol

Ethyl3-(4-methoxy-3-(methylsulfonyl)phenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 10, 180 mg, 0.313 mmol) was dissolved in THE (5 mL) underan atmosphere of nitrogen at 0° C., and lithium aluminum hydride (1 M inTHF) (0.626 mL, 0.626 mmol) was added then the reaction was stirred fora further 3 h. The reaction was quenched by the addition of 2 M sodiumhydroxide (5 mL) and stirred for a further 1 h. The organic phase wasextracted with ethyl acetate (3×10 mL), the organic phase dried througha hydrophobic filter and the solvent removed in vacuo to afford titlecompound. LCMS (method F): rt=0.89, [M+H]⁺=533.

Intermediate 123-(4-Methoxy-3-(methylsulfonyl)phenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde

(3-(4-Methoxy-3-(methylsulfonyl)phenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)methanol(intermediate 11, 112 mg, 0.21 mmol) was dissolved in DCM (2.5 mL),manganese dioxide (32 mg, 0.368 mmol) was added and the reaction stirredat room temp. for 4 h. Further manganese dioxide (183 mg, 2.103 mmol)was added and the reaction stirred at room temp. for a further 16 h. Thereaction mixture was filtered through a CELITE cartridge, washing withDCM (3×5 mL) and the solvent was removed in vacuo to give the titlecompound. LCMS (method F): rt=1.0, [M+H]⁺=531.

Intermediate 13 Ethyl7-((tert-butoxycarbonyl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate

To a solution of ethyl2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 7, 3.8 g, 9.73 mmol) in DCM (25 mL) was added DIPEA (5.1mL, 29.2 mmol), DMAP (1.189 g, 9.73 mmol) and Boc-anhydride (3.39 mL,14.6 mmol) and the reaction was stirred for 16 h at room temp. Thereaction mixture was diluted with DCM (50 mL), washed with water (25mL), dried over sodium suphate, filtered and concentrated. The residuewas dissolved in DCM (30 mL), absorbed on silica gel (5 g) and purifiedby silica gel chromatography (15 g) eluting with ethyl acetate in pet.ether to give the title compound. LCMS (method G): rt=2.14, [M+H]⁺=617.

Intermediate 14 tert-Butyl(5-(hydroxymethyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate

To a solution of ethyl7-((tert-butoxycarbonyl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 13, 500 mg, 0.811 mmol) in ethanol (10 mL) was addedsodium borohydride (92 mg, 2.433 mmol) and the reaction was stirred for3 h at 10° C. The reaction mixture was quenched with 1 M HCl (5 mL), thepH was adjusted to 6, then concentrated. The residue was dissolved inethyl acetate (25 mL), washed with water (20 mL), dried over sodiumsulphate, filtered and concentrated to give the title compound. LCMS(method H): rt=2.01, [M+H]⁺=573.

Intermediate 15 tert-Butyl(5-formyl-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate

DMP (1752 mg, 4.13 mmol) was added in one portion to a stirred solutionof tert-butyl(5-(hydroxymethyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(intermediate 14, 1306 mg, 2.274 mmol) in DCM (7.5 mL). The reaction wasleft to stir for 18 h. Aqueous saturated sodium sulphite (10 mL) wasadded and the reaction was stirred for 2 h at room temp. The reactionmixture was partitioned between DCM (150 mL) and water (150 mL). Theorganic layer was separated and the aqueous extracted with further DCM(2×50 mL). The combined organic layers were washed with aqueoussaturated sodium hydrogen carbonate (100 mL), water (100 mL), passedthrough a hydrophobic frit and then evaporated in vacuo. The residue wasdissolved in the minimum amount of DCM and purified by silica gelchromatography (120 g), eluting with 0-50% ethyl acetate:ethanol (3:1,v/v) in cyclohexane to give the title compound. LCMS (method F):rt=1.27, [M+H]⁺=573.

Intermediate 16 1-Methoxy-2-(methylsulfonyl)benzene

To a stirred solution of (2-methoxyphenyl)(methyl)sulfane (50 g, 324mmol) in DCM (1 L) at 0° C. under nitrogen atmosphere was added m-CPBA(140 g, 810 mmol). The reaction mixture was allowed to stir at roomtemp. for 2 h. The reaction mixture was diluted with DCM (300 mL),washed with saturated aqueous sodium carbonate (2×500 mL). The aqueouslayer was extracted with DCM (200 mL). The combined organics were driedover anhydrous sodium sulphate, filtered and evaporated under reducedpressure to afford the title compound. LCMS (method I): rt=2.28,[M+H]⁺=187.

Intermediate 17 2-((2-Methoxyphenyl)sulfonyl)ethanol

To a stirred solution of 1-methoxy-2-(methylsulfonyl)benzene(intermediate 16, 25 g, 123 mmol) in THE (250 mL) at −78° C. undernitrogen atmosphere was added n-butyllithium (115 mL, 184 mmol) dropwiseand the reaction mixture was stirred at −78° C. for 30 min then cooledto 0° C. Paraformaldehyde (73.6 g, 2450 mmol) was added portionwise thenthe reaction mixture was stirred at 0° C. for 2 h. The reaction mixturewas quenched with ammonium chloride solution (120 mL), extracted withethyl acetate (2×200 mL). The combined organics were washed with brine(150 mL) and dried over anhydrous sodium sulphate, filtered andevaporated under reduced pressure. The crude compound was preabsorbedonto silica gel (4 g) and purified by silica gel chromatography (10 gcolumn, 80% ethyl acetate in hexane) to afford the title compound. LCMS(method C): rt=1.16, [M+H]⁺=217.

Intermediate 18 2-((5-Bromo-2-methoxyphenyl)sulfonyl)ethanol

To a stirred solution of 2-((2-methoxyphenyl)sulfonyl)ethanol(intermediate 17, 10 g, 46.2 mmol) in DMF (100 mL) under nitrogenatmosphere at room temp. was added recrystallised NBS (16.46 g, 92mmol). The reaction mixture was warmed to 50° C. for 18 h. The reactionmixture was cooled to room temp. and diluted with ethyl acetate (300 mL)and washed with ice cold water (2×500 mL). The organic layer wasseparated, and the aqueous layer was again extracted with ethyl acetate(300 mL). The combined organic layers were washed with brine (300 mL)and dried over sodium sulphate, filtered and concentrated under reducedpressure. The crude compound was preabsorbed onto silica gel (10 g) andpurified by silica gel chromatography (90 g column, 40% ethyl acetate inhexane) to afford the title compound. LCMS (method C): rt=1.85,[M+H]⁺=295.

Intermediate 192-((2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethanol

To a stirred solution of 2-((5-bromo-2-methoxyphenyl)sulfonyl)ethanol(intermediate 18, 10 g, 33.9 mmol) in 1,4-dioxane (150 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (17.2 g,67.8 mmol) and potassium acetate (9.98 g, 102 mmol) at room temp., thenthe reaction mixture was degassed with nitrogen for 15 min.PdCl₂(dppf)-DCM adduct (2.77 g, 3.39 mmol) was added and the reactionmixture heated at 100° C. for 3 h in a sealed tube. The reaction mixturewas filtered on a CELITE pad and the CELITE was washed with ethylacetate (2×100 mL). The combined organics were concentrated underreduced pressure. The reaction was repeated on the same scale. The twobatches of crude product were blended and dissolved in DCM (100 mL). Themixture was treated with charcoal (5 g) and refluxed for 10 min thenfiltered on a CELITE pad. The CELITE was washed with DCM (2×100 mL). Thecombined organics were concentrated under reduced pressure. The crudeproduct was purified by silica gel chromatography (ethyl acetate in pet.ether) to afford the title compound. LCMS (method C): rt=2.17,[M+H]⁺=343.

Intermediate 20 tert-Butyl(5-formyl-3-(3-((2-hydroxyethyl)sulfonyl)-4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate

A microwave vial was charged with tert-butyl(5-formyl-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(intermediate 15, 487 mg, 0.851 mmol),2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethan-1-ol(intermediate 19, 415 mg, 1.03 mmol), PdCl₂(dppf) (64 mg, 0.087 mmol)and potassium fluoride (151 mg, 2.6 mmol) in 1,4-dioxane (2 mL) andwater (1 mL). The reaction vessel was sealed and heated in a microwavereactor at 100° C. for a total of 1.5 h. The reaction mixture was passedover CELITE, washed with methanol (50 mL) and evaporated in vacuo. Theresidue was dissolved in DCM (30 mL) and partitioned with water (15 mL).The organic layer was separated and the aqueous extracted with furtherDCM (2×20 mL). The combined organic layers were passed through ahydrophobic frit and evaporated in vacuo. The residue was purified bysilica chromatography (80 g), eluting with 50-100% ethyl acetate:ethanol(3:1, v/v containing 1% triethylamine) in cyclohexane over 20 CV to givethe title compound. LCMS (method F): rt=1.06, [M+H]⁺=661.

Intermediate 212-(3-Iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol

Ethyl3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 7, 275 mg, 0.533 mmol) was stirred in THE (5 mL) at 0° C.under nitrogen. Methylmagnesium bromide (1 M in dibutyl ether) (1.75 mL,1.75 mmol) was added over 2 min and the mixture allowed to warm to roomtemp. then left for 4.5 h. The reaction mixture was quenched with water(2 mL) then partitioned with DCM (50 mL) and water (50 mL). The organicphase was collected and the aqueous washed with DCM (50 mL) and thenethyl acetate (50 mL). The combined organic layers were passed through ahydrophobic frit and evaporated to dryness. The residue was loaded inDCM (2 mL) onto a silica gel column (40 g) and eluted with 10-60% ethylacetate:ethanol (3:1, v/v containing 1% triethylamine) in cyclohexane togive the title compound. LCMS (method J): rt=0.7, [M+H]⁺=503.

Intermediate 22 5-Bromo-2-chloro-N-(3-hydroxypropyl)-N-methylbenzamide

To a stirred solution of 5-bromo-2-chlorobenzoic acid (12.5 g, 53.1mmol) in THE (100 mL) was added 3-(methylamino)propan-1-ol (5.21 g, 58.4mmol), DIPEA (27.8 mL, 159 mmol) and HATU (22.2 g, 58.4 mmol) and thereaction mixture was stirred at room temp. for 18 h. The reactionmixture was diluted with water (100 mL) and extracted with ethyl acetate(200 mL). The organic layer was dried with anhydrous sodium sulphate andconcentrated under reduced pressure. The crude product was dissolved inDCM (50 mL), pre-absorbed onto silica gel (50 g) and purified by silicagel chromatography (150 g, 100% ethyl acetate) to afford the titlecompound. LCMS (method K): rt=5.30, [M+H]⁺=306.

Intermediate 232-Chloro-N-(3-hydroxypropyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

To a stirred solution of5-bromo-2-chloro-N-(3-hydroxypropyl)-N-methylbenzamide (intermediate 22,10 g, 32.6 mmol) in 1,4-dioxane (100 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (9.69 g,38.2 mmol), potassium acetate (9.60 g, 98 mmol) and the reaction wasdegassed with argon for 30 min. PdCl₂(dppf)-DCM adduct (0.266 g, 0.326mmol) was added and the mixture was degassed for 20 min. The reactionmixture was heated to 100° C. for 18 h. The reaction mixture was cooledto room temp. and filtered through a CELITE pad and washed with 10%methanol in DCM then concentrated under reduced pressure. The crudeproduct was dissolved in DCM (50 mL), pre-absorbed onto florisil (50 g)and purified by silica gel chromatography (250 g, 0-100% ethyl acetatein pet. ether) to afford the title compound. LCMS (method L): rt=2.45,[M+H]⁺=354.

Intermediate 24(S)-(5-Bromo-2-methoxyphenyl)(3-hydroxypyrrolidin-1-yl)methanone

DIPEA (1.134 mL, 6.49 mmol) was added to a solution of5-bromo-2-methoxybenzoic acid (500 mg, 2.164 mmol) and HATU (987 mg, 2.6mmol) in 2-MeTHF (10 mL) and the reaction was left to stir at room temp.for 30 min under nitrogen. (S)-pyrrolidin-3-ol (226 mg, 2.6 mmol) wasthen added and the reaction was left to stir at room temp. overnightwith the addition of DMF (5 mL). The reaction mixture was concentratedunder reduced pressure, diluted with saturated aqueous sodium hydrogencarbonate solution (50 mL) and 5% lithium chloride solution (50 mL), andextracted with ethyl acetate (2×100 mL). The combined organic layerswere passed through a hydrophobic frit, concentrated under reducedpressure and further dried under a stream of nitrogen overnight. Theresidue was loaded in DCM and purified by silica chromatography (80 g)eluting with ethyl acetate:ethanol (3:1, v/v, containing 1%triethylamine) in ethyl acetate (0%, 2 CV; 0-100%, 12 CV) to give thetitle compound. LCMS (method F): rt=0.73, [M+H]⁺=300.

Intermediate 25(S)-(3-Hydroxypyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

(S)-(5-Bromo-2-methoxyphenyl)(3-hydroxypyrrolidin-1-yl)methanone(intermediate 24, 750 mg, 2.249 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (628 mg,2.474 mmol), potassium acetate (662 mg, 6.75 mmol), PdCl₂(dppf) (165 mg,0.225 mmol), and 1,4-dioxane (6 mL) were combined and placed undernitrogen by evacuation-refill. The mixture was heated in a microwavereactor at 100° C. for 1 h. The solvent was removed from the reactionmixture under reduced pressure. The residue was suspended in ethylacetate (50 mL) and water (30 mL) and filtered through CELITE, rinsingwith further ethyl acetate (50 mL). The solution was diluted with brine(20 mL) and the aqueous layer was washed with further ethyl acetate (100mL), the combined organic layers were passed through a hydrophobic fritand the solvent removed under reduced pressure to give the titlecompound. LCMS (method J): rt=0.85, [M+H]⁺=348.

Intermediate 26 tert-Butyl(5-(1-hydroxyethyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate

tert-Butyl(5-formyl-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(intermediate 15, 465 mg, 0.812 mmol) was dissolved in THE (10 mL) andcooled to −78° C. Methylmagnesium bromide (1 M in dibutyl ether) (0.85mL, 0.85 mmol) was added dropwise over 2 min. After 1 h 45 minmethylmagnesium bromide (1 M in dibutyl ether) (0.203 mL, 0.203 mmol)was added and the mixture stirred at −78° C. for a further 3 h.Saturated aqueous ammonium chloride (5 mL) and water (10 mL) were addedand the mixture was stirred for 10 min while warming to room temp. DCM(20 mL) was added and the mixture transferred and the organic layer wascollected. The aqueous was further washed with DCM (2×20 mL) and thecombined organic layers were passed through a hydrophobic frit andevaporated to dryness. The residue was wet-loaded in DCM (1.5 mL) onto asilica gel column and eluted with 50-60% ethyl acetate in cyclohexaneover 30 CV and then 60-85% ethyl acetate in cyclohexane over 10 CV. Thefractions containing product were combined and evaporated to drynessthen triturated with diethyl ether to give the title compound. LCMS(method F): rt=1.2, [M+H]⁺=589.

Intermediate 27 5-Bromo-N-(3-hydroxypropyl)-2-methoxy-N-methylbenzamide

HATU (458.3 mg, 1.205 mmol) and DIPEA (0.655 mL, 3.75 mmol) were addedto a stirred solution of 5-bromo-2-methoxybenzoic acid (288.9 mg, 1.250mmol) in THE (10 mL) at room temp. After 10 min3-(methylamino)propan-1-ol (0.146 mL, 1.500 mmol) was added. After 2 hthe solvent was removed in vacuo and the resulting residue diluted withethyl acetate (10 mL) and water (10 mL). The separated aqueous phase wasfurther extracted with ethyl acetate (2×10 mL). The combined organiclayers were passed through a hydrophobic frit and the solvent wasremoved in vacuo to give the title compound. LCMS (method F): rt=0.78,[M+H]⁺=303.

Intermediate 28N-(3-Hydroxypropyl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.114 g,4.39 mmol), potassium acetate (1.077 g, 10.97 mmol), PdCl₂(dppf). DCMadduct (0.299 g, 0.366 mmol) and 1,4-dioxane (7 mL) were combined andplaced under nitrogen (cycled between vacuum/nitrogen 3 times). Asolution of 5-bromo-N-(3-hydroxypropyl)-2-methoxy-N-methylbenzamide(intermediate 27, 1.7 g, 3.66 mmol) in 1,4-dioxane (7 mL) was added andthe mixture cycled between vacuum/nitrogen 3 times. The reaction wasthen heated at 100° C. in a microwave reactor for 90 min. After cooling,the mixture was filtered through CELITE, washed with DCM (50 mL) and thesolvent removed in vacuo. The resulting residue was dissolved in ethylacetate (60 mL), water (60 mL) and brine (20 mL). The separated aqueouslayer was re-extracted with ethyl acetate (2×30 mL). The combinedorganic layers were passed through a hydrophobic frit and the solventremoved in vacuo. The crude product was purified by silica gel columnchromatography eluting with 50-100% ethyl acetate in cyclohexane to givethe title compound. LCMS (method F): rt=0.89, [M+H]⁺=350.

Intermediate 29 5-Bromo-N-ethyl-N-(2-hydroxyethyl)-2-methoxybenzamide

DIPEA (1.2 mL, 6.87 mmol) and HATU (980 mg, 2.58 mmol) were added to astirred solution of 5-bromo-2-methoxybenzoic acid (500 mg, 2.164 mmol)in 2-MeTHF (10 mL). After 15 min 2-(ethylamino)ethan-1-ol (0.25 mL, 2.56mmol) was added and the reaction left to stir overnight. The mixture waspartitioned between ethyl acetate (50 mL) and saturated aqueous sodiumbicarbonate (50 mL). The aqueous phase was further extracted with ethylacetate (50 mL). The combined organic phase was washed with saturatedaqueous sodium bicarbonate (50 mL) and the solvent removed under reducedpressure. The residue was purified by silica gel chromatography elutingwith 0-100% ethyl acetate:ethanol (3:1, containing 1% triethylamine) incyclohexane to give the title compound. LCMS (method F): rt=0.8,[M+H]⁺=302.

Intermediate 30N-Ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

5-Bromo-N-ethyl-N-(2-hydroxyethyl)-2-methoxybenzamide (intermediate 29,1.2 g, 3.97 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.18 g,4.65 mmol), PdCl₂(dppf) (0.301 g, 0.411 mmol), potassium acetate (1.17g, 11.92 mmol) and 1,4-dioxane (8 mL) were combined and placed undernitrogen by evacuation and refill. The mixture was heated at 100° C. ina microwave reactor for 1.5 h. After cooling, the reaction mixture wasfiltered through CELITE, washed with methanol (250 mL) and the solventremoved under reduced pressure. The residue was re-dissolved in DCM (30mL) and partitioned with water (30 mL). The aqueous layer wasre-extracted with DCM (3×30 mL) and the combined organic extracts passedthrough a hydrophobic frit and evaporated to dryness to give the titlecompound. LCMS (method F): rt 0.92, [M+H]⁺=350.

Intermediate 31 5-Bromo-2-chloro-N-ethyl-N-(2-hydroxyethyl)benzamide

DIPEA (1.1 mL, 6.30 mmol) and HATU (1.05 g, 2.76 mmol) were added to astirred solution of 5-bromo-2-chlorobenzoic acid (509 mg, 2.162 mmol) in2-MeTHF (10 mL) and the reaction was left to stir at room temp. for 15min. 2-(Ethylamino)ethan-1-ol (0.25 mL, 2.56 mmol) was added and thereaction stirred over the weekend. The mixture was partitioned betweenethyl acetate (50 mL) and saturated aqueous sodium bicarbonate (50 mL).The aqueous phase was further washed with ethyl acetate (50 mL) and thecombined organic phases washed with saturated aqueous sodium bicarbonate(50 mL) and the solvent removed under reduced pressure. The crude waspurified by silica gel column chromatography eluting with 20-100% ethylacetate in cyclohexane. The fractions containing product were combinedand evaporated to dryness. The residue was further purified by reversephase column chromatography eluting with 20-60% acetonitrile (containing0.01% ammonia) in 10 mM ammonium bicarbonate in water adjusted to pH 10with ammonia solution to give the title compound. LCMS (method E):rt=0.85, [M+H]⁺=306.

Intermediate 322-Chloro-N-ethyl-N-(2-hydroxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

4,4,4′,4′,5,5,5′,5′-Octamethyl-2,2′-bi(1,3,2-dioxaborolane) (462 mg,1.819 mmol), 5-bromo-2-chloro-N-ethyl-N-(2-hydroxyethyl)benzamide(intermediate 31, 453 mg, 1.478 mmol), PdCl₂(dppf) (111 mg, 0.152 mmol)and potassium acetate (445 mg, 4.53 mmol) were combined in 1,4-dioxane(4 mL). The mixture was degassed and heated at 100° C. in a microwavereactor for 1 h, three times. After cooling, the mixture was filteredthrough CELITE, washed with methanol (100 mL) and the solvent removed invacuo. The residue was partitioned between DCM (20 mL) and water (10mL). The separated aqueous layer was further washed with DCM (2×10 mL).The combined organic layers were passed through a hydrophobic frit andthe solvent removed in vacuo to give the title compound. LCMS (methodD): rt=1.05, [M+H]⁺=354.

Intermediate 335-Bromo-2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide

HATU (1.391 g, 3.66 mmol) and DIPEA (1.72 mL, 9.85 mmol) were added to astirred suspension of 5-bromo-2-methoxybenzoic acid (0.752 g, 3.25 mmol)in THE (10 mL) and stirred for 20 min.N-Methyltetrahydro-2H-pyran-4-amine (0.382 g, 3.32 mmol) was added andthe reaction mixture left to stir for 18 h. The solvent was removed invacuo. The reaction mixture was partitioned between DCM (50 mL) andwater (50 mL), the aqueous phase was extracted further with DCM (2×20mL) and the organic phase was filtered through a hydrophobic frit andthe solvent removed in vacuo. The residue was dissolved in the minimumamount of DCM and purified by silica gel chromatography (120 g) elutingwith 0-100% ethyl acetate:ethanol (3:1, v/v) in cyclohexane to give thetitle compound. LCMS (method F): rt=0.89, [M+H]⁺=328.

Intermediate 342-Methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

5-Bromo-2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide(intermediate 33, 746 mg, 2.273 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (692 mg,2.73 mmol), PdCl₂(dppf). DCM (194 mg, 0.238 mmol), potassium acetate(664 mg, 6.77 mmol) and 1,4-dioxane (10 mL) were combined and heated ina microwave reactor at 100° C. for 1 h. The reaction mixture wasfiltered through CELITE and the solvent removed in vacuo. The residuewas partitioned between water (25 mL) and DCM (25 mL), the aqueous phasewas extracted further with DCM (2×15 mL) and the organic phase wasfiltered through a hydrophobic frit, then evaporated to dryness to givethe title compound. LCMS (method F): rt=1.01, [M+H]⁺=376.

Intermediate 35 5-Bromo-N-(3-hydroxypropyl)-N,2-dimethylbenzamide

5-Bromo-2-methylbenzoic acid (504 mg, 2.344 mmol), HATU (1053 mg, 2.77mmol) and DIPEA (0.5 mL, 2.86 mmol) in DMF (4 mL) were stirred at roomtemp. for 30 min after which 3-(methylamino)propan-1-ol (0.275 mL, 2.83mmol) was added. After 3 h the mixture was partitioned between ethylacetate (20 mL) and water (15 mL). The separated aqueous layer wasfurther extracted with ethyl acetate (15 mL). The combined organiclayers were washed with 5% aqueous lithium chloride solution (2×10 mL),water (10 mL) and brine (10 mL). The organic layer was passed through ahydrophobic frit and the solvent removed in vacuo. The crude waspurified by silica gel column chromatography eluting with 50-100% ethylacetate in cyclohexane to give the title compound. LCMS (method F):rt=0.80, [M+H]⁺=286.

Intermediate 36N-(3-Hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Potassium acetate (636 mg, 6.48 mmol),5-bromo-N-(3-hydroxypropyl)-N,2-dimethylbenzamide (intermediate 35, 685mg, 2.154 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (663 mg,2.61 mmol) and PdCl₂(dppf) (131 mg, 0.179 mmol) were combined in1,4-dioxane (5 mL). The mixture was placed under nitrogen by cyclingbetween vacuum and nitrogen five times and heated in a microwave reactorat 100° C. for 1 h. After cooling, the solvent was removed in vacuo andthe residue partitioned between DCM (30 mL) and water (20 mL). Theseparated aqueous layer was further washed with DCM (2×20 mL) and thecombined organic layers passed through a hydrophobic frit and thesolvent removed in vacuo to give the title compound. LCMS (method J):rt=0.97, [M+H]⁺=334.

Intermediate 37(S)-(5-bromo-2-chlorophenyl)(3-hydroxypyrrolidin-1-yl)methanone

Prepared in a similar manner to intermediate 33, using5-bromo-2-chlorobenzoic acid (480 mg, 2.039 mmol) and(S)-pyrrolidin-3-ol (178 mg, 2.039 mmol) to give the title compound.LCMS (method F): rt=0.73, [M+H]⁺=303.

Intermediate 38(S)-(2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(3-hydroxypyrrolidin-1-yl)methanone

Prepared in a similar manner to intermediate 32, using(S)-(5-bromo-2-chlorophenyl)(3-hydroxypyrrolidin-1-yl)methanone(intermediate 37), to give the title compound. LCMS (method F): rt=0.72,[M+H]⁺=352.

Intermediate 39(S)-5-Bromo-N-(1-hydroxypropan-2-yl)-2-methoxy-N-methylbenzamide

Prepared in a similar manner to intermediate 35, using5-bromo-2-methoxybenzoic acid (0.747 g, 3.23 mmol) and(S)-2-(methylamino)propan-1-ol (0.321 g, 3.6 mmol) to give the titlecompound. LCMS (method F): rt=0.77, [M+H]⁺=302.

Intermediate 40(S)—N-(1-Hydroxypropan-2-yl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 32, using(S)-5-bromo-N-(1-hydroxypropan-2-yl)-2-methoxy-N-methylbenzamide(intermediate 39) to give the title compound. LCMS (method F): rt=0.89,[M+H]⁺=350.

Intermediate 41 Ethyl3-bromo-7-chloro-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate

Prepared in a similar manner to intermediate 6, using NBS, to give thetitle compound. LCMS (method J): rt=1.11, [M+H]⁺=320.

Intermediate 42 Ethyl3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate

Ethyl 3-bromo-7-chloro-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 41, 685 mg, 2.15 mmol),(3-(1-methyl-1H-imidazol-2-yl)phenyl)methanamine (intermediate 3, 443mg, 2.365 mmol) and DIPEA (0.751 mL, 4.3 mmol) were stirred in DMSO (5mL) at 80° C. under nitrogen for 3.5 h. After cooling, the mixture waspoured onto ice cold water and the precipitate collected by filtration.The cake was then dissolved in DCM, dried under reduced pressure andtriturated with diethyl ether to give the title compound. LCMS (methodF): rt=1.06, [M+H]⁺=469.

Alternative Preparation of Intermediate 42

Ethyl 3-bromo-7-chloro-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 41, 50 g, 157 mmol),(3-(1-methyl-1H-imidazol-2-yl)phenyl)methanamine (intermediate 3, 35.3g, 188 mmol) and DIPEA (54.8 mL, 314 mmol) were stirred in DMSO (500 mL)at 80° C. for 3 h. After cooling, the reaction mixture was poured intoice cold water and the precipitate collected by filtration. The solidobtained was triturated with diethyl ether (500 mL), filtered and driedto afford the title compound. LCMS (method C): rt=1.44, [M+H]⁺=469.

Intermediate 432-(3-Bromo-2-methyl-7-(3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol

Ethyl3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 42, 1.76 g, 3.75 mmol) was stirred in THF (35 mL) at 0° C.under nitrogen. Methylmagnesium chloride (3 M in THF) (5.6 mL, 16.8mmol) was added over 10 min and the mixture stirred at 0° C. for 30 min.The mixture was warmed to room temp. and stirred overnight. The reactionmixture was quenched with aqueous saturated ammonium chloride (5 mL),then partitioned with DCM (100 mL) and aqueous saturated ammoniumchloride (100 mL). The organic phase was collected and the aqueouswashed with DCM (2×25 mL). The combined organic layers were passedthrough a hydrophobic frit and evaporated to dryness. The residue wasstirred in THF (35 mL) under nitrogen at 0° C. Methylmagnesium chloride(3 M in THF) (3.75 mL, 11.25 mmol) was added over 10 min and the mixturestirred at 0° C. for 40 min after which it was stirred at room temp. for20 min. The reaction mixture was quenched with aqueous saturatedammonium chloride (5 mL) then partitioned with DCM (100 mL) and aqueoussaturated ammonium chloride (100 mL). The organic phase was collectedand the aqueous washed with DCM (2×25 mL). The combined organic layerswere passed through a hydrophobic frit, concentrated under reducedpressure and dried for 4 days on the high-vac line to give the titlecompound. LCMS (method J): rt=0.65, [M+H]⁺=455.

Alternative Preparation of Intermediate 43

Ethyl3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 42, 81 g, 173 mmol) was stirred in DCM (300 mL) and THF(100 mL) at 5° C. under nitrogen. Methylmagnesium chloride (3 M in THF)(230 mL, 690 mmol) was added dropwise over 45 min maintaining theinternal temperature below 15° C. and stirred for an additional 10 min.The mixture was quenched with saturated aqueous ammonium chloride (400mL) and partitioned between DCM (2 L) and water (2 L). The organic phasewas dried over magnesium sulphate and concentrated under reducedpressure. The resulting residue was dissolved in DCM (500 mL) and THE(250 mL) and cooled to 0° C. under nitrogen. Methylmagnesium chloride (3M in THF) (173 mL, 518 mmol) was added dropwise over 1 h, maintainingthe internal temperature below 10° C. After addition, the mixture wasstirred at 5° C. for 10 min. The mixture was quenched with saturatedaqueous ammonium chloride (400 mL) and partitioned between DCM (2 L) andwater (2 L). The organic phase was dried over magnesium sulphate andconcentrated under reduced pressure to give the title compound. LCMS(method J): rt=0.60, [M+H]⁺=455.

Intermediate 44(S)-5-Bromo-N-(1-hydroxypropan-2-yl)-N,2-dimethylbenzamide

Prepared in a similar manner to intermediate 33, using5-bromo-2-methylbenzoic acid (800 mg, 3.72 mmol) and(S)-2-(methylamino)propan-1-ol (332 mg, 3.72 mmol) to give the titlecompound. LCMS (method F): rt=0.82, [M+H]⁺=286.

Intermediate 45(S)—N-(1-Hydroxypropan-2-yl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 32, using(S)-5-bromo-N-(1-hydroxypropan-2-yl)-N,2-dimethylbenzamide (intermediate44) to give the title compound. LCMS (method F): rt=0.92, [M+H]⁺=334.

Intermediate 46 5-Bromo-2-methoxy-N,N-dimethylbenzamide

Prepared in a similar manner to intermediate 33, using5-bromo-2-methoxybenzoic acid (483 mg, 2.091 mmol) and dimethylamine (2M in THF) (1.254 mL, 2.509 mmol) to give the title compound. LCMS(method F): rt=0.85, [M+H]⁺=258.

Intermediate 472-Methoxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 32, using5-bromo-2-methoxy-N,N-dimethylbenzamide (intermediate 46) to give thetitle compound. LCMS (method F): rt=1.01, [M+H]⁺=306.

Intermediate 48(R)-(5-Bromo-2-chlorophenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

Prepared in a similar manner to intermediate 33, using5-bromo-2-chlorobenzoic acid (503 mg, 2.136 mmol) and(R)-pyrrolidin-2-ylmethanol to give the title compound. LCMS (method F):rt=0.89, [M+H]⁺=320.

Intermediate 49(R)-(2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

Prepared in a similar manner to intermediate 32, using(R)-(5-Bromo-2-chlorophenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone(intermediate 48) to give the title compound. LCMS (method F): rt=0.94,[M+H]⁺=366.

Intermediate 50(R)-(5-Bromo-2-methylphenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

5-Bromo-2-methylbenzoic acid (534 mg, 2.483 mmol), HATU (1074 mg, 2.82mmol) and DIPEA (0.520 mL, 2.98 mmol) in DMF (1 mL) and THE (5 mL) werestirred at room temp. for 30 min when (R)-pyrrolidin-2-ylmethanol (0.3mL, 3.04 mmol) was added in one portion. The reaction was stirred for 18h. The solvent was removed in vacuo. The residue was dissolved in ethylacetate (40 mL) and partitioned with water (20 mL). The organic layerwas separated and washed with 5% aqueous lithium chloride solution (2×10mL), water (10 mL) and brine (10 mL). The organic layer was then passedthrough a hydrophobic frit and the solvent removed in vacuo. The residuewas dissolved in a minimal amount of DCM and loaded onto a silica column(80 g) and eluted over 12 CV with 0-100% ethyl acetate:ethanol (3:1,v/v, containing 1% triethylamine) in cyclohexane to give the titlecompound. LCMS (method F): rt=0.87, [M+H]⁺=298.

Intermediate 51(R)-(2-(Hydroxymethyl)pyrrolidin-1-yl)(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

Prepared in a similar manner to intermediate 36, using(R)-(5-bromo-2-methylphenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone(intermediate 50) to give the title compound. LCMS (method F): rt=1.02,[M+H]⁺=346.

Intermediate 52 5-Bromo-N-(2-hydroxyethyl)-2-methoxy-N-methylbenzamide

Prepared in a similar manner to intermediate 33, using5-bromo-2-methoxybenzoic acid (400 mg, 1.731 mmol) and2-(methylamino)ethan-1-ol (0.167 mL, 2.078 mmol) to give the titlecompound. LCMS (method F): rt=0.72, [M+H]⁺=288.

Intermediate 53N-(2-Hydroxyethyl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 32 using5-bromo-N-(2-hydroxyethyl)-2-methoxy-N-methylbenzamide (intermediate 52)to give the title compound. LCMS (method F): rt=0.85, [M+H]⁺=336.

Intermediate 54(5-Bromo-2-methoxyphenyl)(3-hydroxy-3-methylpyrrolidin-1-yl)methanone

Prepared in a similar manner to intermediate 33 using5-bromo-2-methoxybenzoic acid (503 mg, 2.177 mmol) and3-methylpyrrolidin-3-ol (244 mg, 2.412 mmol) to give the title compound.LCMS (method F): rt=0.76, [M+H]⁺=314.

Intermediate 55(3-Hydroxy-3-methylpyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

Prepared in a similar manner to intermediate 32 using(5-bromo-2-methoxyphenyl)(3-hydroxy-3-methylpyrrolidin-1-yl)methanone(intermediate 54) to give the title compound. LCMS (method F): rt=0.91,[M+H]⁺=362.

Intermediate 56 (5-Bromo-2-methoxyphenyl)(1,4-oxazepan-4-yl)methanone

Prepared in a similar manner to intermediate 33, using5-bromo-2-methoxybenzoic acid (528 mg, 2.285 mmol) and 1,4-oxazepane(272 mg, 2.69 mmol) to give the title compound. LCMS (method F):rt=0.87, [M+H]⁺=316.

Intermediate 57(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(1,4-oxazepan-4-yl)methanone

Prepared in a similar manner to intermediate 32, using(5-bromo-2-methoxyphenyl)(1,4-oxazepan-4-yl)methanone (intermediate 56)to give the title compound. LCMS (method F): rt=1.0, [M+H]⁺=362.

Intermediate 58(S)-(5-Bromo-2-methylphenyl)(3-hydroxypyrrolidin-1-yl)methanone

Prepared in a similar manner to intermediate 29, using5-bromo-2-methylbenzoic acid (493 mg, 2.293 mmol) and(S)-pyrrolidin-3-ol (0.23 mL, 2.77 mmol) to give the title compound.LCMS (method F): rt=0.75, [M+H]⁺=284.

Intermediate 59(S)-(3-Hydroxypyrrolidin-1-yl)(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

Prepared in a similar manner to intermediate 32, using(S)-(5-bromo-2-methylphenyl)(3-hydroxypyrrolidin-1-yl)methanone(intermediate 58) to give the title compound. LCMS (method F): rt=0.87,[M+H]⁺=332.

Intermediate 60(S)-(5-Bromo-2-methoxyphenyl)(3-methylmorpholino)methanone

Prepared in a similar manner to intermediate 50, using5-bromo-2-methoxybenzoic acid (505 mg, 2.186 mmol) and(S)-3-methylmorpholine (251 mg, 2.481 mmol) to give the title compound.LCMS (method F): rt=0.92, [M+H]⁺=314.

Intermediate 61(S)-(2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(3-methylmorpholino)methanone

Prepared in a similar manner to intermediate 32, using(S)-(5-bromo-2-methoxyphenyl)(3-methylmorpholino)methanone (intermediate60) to give the title compound. LCMS (method F): rt=1.04, [M+H]⁺=362.

Intermediate 62(5-Bromo-2-methylphenyl)(3-hydroxy-3-methylpyrrolidin-1-yl)methanone

Prepared in a similar manner to intermediate 33, using5-bromo-2-methylbenzoic acid (394 mg, 1.832 mmol) and3-methylpyrrolidin-3-ol (222 mg, 2.199 mmol) to give the title compound.

LCMS (method F): rt=0.81, [M+H]⁺=298.

Intermediate 63(3-Hydroxy-3-methylpyrrolidin-1-yl)(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

Prepared in a similar manner to intermediate 32, using(5-bromo-2-methylphenyl)(3-hydroxy-3-methylpyrrolidin-1-yl)methanone(intermediate 62) to give the title compound. LCMS (method F): rt=0.91,[M+H]⁺=346.

Intermediate 64 Ethyl7-((3-(1H-pyrazol-1-yl)benzyl)amino)-3-bromo-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate

Prepared in a similar manner to intermediate 42, using(3-(1H-pyrazol-1-yl)phenyl)methanamine (available from Sigma-AldrichInc.) to give the title compound. LCMS (method F): rt=1.21, [M+H]⁺=455.

Intermediate 65 Ethyl7-((3-(1H-pyrazol-1-yl)benzyl)amino)-3-bromo-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate

Prepared in a similar manner to intermediate 43, using ethyl7-((3-(1H-pyrazol-1-yl)benzyl)amino)-3-bromo-2-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 64) to give the title compound. LCMS (method F): rt=1.20,[M+H]⁺=441.

Intermediate 66(R)-(5-Bromo-2-methoxyphenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

Prepared in a similar manner to intermediate 35, using5-bromo-2-methoxybenzoic acid and (R)-pyrrolidin-2-ylmethanol to givethe title compound. LCMS (method F): rt=0.83, [M+H]⁺=314.

Intermediate 67(R)-(2-(Hydroxymethyl)pyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

Prepared in a similar manner to intermediate 36, using(R)-(5-bromo-2-methoxyphenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone(intermediate 66) to give the title compound. LCMS (method F): rt=1.02,[M+H]⁺=362.

Intermediate 68 5-Bromo-2-chloro-N-(2-hydroxyethyl)-N-methylbenzamide

Prepared in a similar manner to intermediate 29, using5-bromo-2-chlorobenzoic acid and 2-(methylamino)ethan-1-ol in THF, togive the title compound. LCMS (method F): rt=0.77, [M+H]⁺=294.

Intermediate 692-Chloro-N-(2-hydroxyethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 36, using Intermediate 68,to give the title compound. LCMS (method F): rt=0.75, [M+H]⁺=340.

Intermediate 70 5-Bromo-N-(2-hydroxyethyl)-N,2-dimethylbenzamide

Prepared in a similar manner to Intermediate 29, using5-bromo-2-methylbenzoic acid and 2-(methylamino)ethan-1-ol, to give thetitle compound. LCMS (method F): rt=0.76, [M+H]⁺=274.

Intermediate 71N-(2-Hydroxyethyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 36, using Intermediate 70,to give the title compound. LCMS (method F): rt=0.85, [M+H]⁺=320.

Intermediate 72 5-Bromo-N-(2-hydroxyethyl)-N,2-dimethylbenzamide

Prepared in a similar manner to intermediate 29, using5-bromo-2-methylbenzoic acid and 2-(ethylamino)ethan-1-ol, in THF, togive the title compound. LCMS (method F): rt=0.84, [M+H]⁺=286.

Intermediate 73N-Ethyl-N-(2-hydroxyethyl)-2-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 36, using Intermediate 72,to give the title compound. LCMS (method F): rt=0.95, [M+H]⁺=334.

Intermediate 74 Ethyl2-(2-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetate

To a stirred solution of 5-methyl-1H-pyrazol-3-amine (25 g, 257 mmol) in1,4-dioxane (150 mL), was added diethyl 3-oxopentanedioate (56.8 mL, 309mmol), followed by acetic acid (7.37 mL, 129 mmol) at room temp. Thereaction mixture was stirred at 100° C. for 6 h. The mixture was allowedto cool to room temp. The solids were collected by filtration, washedwith ethyl ether, and dried to give the title compound. LCMS (method H):rt=1.55, [M+H]⁺=236.

Intermediate 75 Ethyl2-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)acetate

To a stirred solution of ethyl2-(2-methyl-7-oxo-4,7-dihydropyrazolo[1,5-a]pyrimidin-5-yl)acetate(Intermediate 74, 22.5 g, 96 mmol) in acetonitrile (250 mL), were addedDIPEA (33.4 mL, 191 mmol), N-methylmorpholine (0.105 mL, 0.956 mmol) andPOCl₃ (17.83 mL, 191 mmol) at 0° C. The reaction mixture was stirred atroom temp. for 24 h. After completion of the reaction, the mixture wasconcentrated, and then poured onto ice/water. The mixture wasneutralized with sodium bicarbonate and extracted with ethyl acetate(2×300 mL). The combined organic layers were washed with brine, driedover sodium sulfate, filtered and concentrated under reduced pressure.The residue was purified by silica chromatography (0-20% ethyl acetatein hexanes) to give the title compound. LCMS (method H): rt=2.05,[M+H]⁺=254.

Intermediate 76 Ethyl2-(7-chloro-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)acetate

To a stirred solution of ethyl2-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)acetate (Intermediate75, 8 g, 31.5 mmol) in DMF (160 mL) was added N-iodosuccinimide (7.09 g,31.5 mmol) at 0° C. The resulting reaction mixture was stirred at roomtemp. for 1 h. The reaction mixture was poured onto ice-cooled water andthe precipitated solid was collected by filtration. The residue waspurified by silica chromatography (0-10% ethyl acetate in hexanes) togive the title compound. LCMS (method H): rt=2.43, [M+H]⁺=380.

Intermediate 77 Ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)acetate

A mixture of ethyl2-(7-chloro-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)acetate(Intermediate 76, 6 g, 15.81 mmol),(3-(1-methyl-1H-imidazol-2-yl)phenyl)methanamine (intermediate 3, 3.55g, 18.97 mmol) and DIPEA (5.52 mL, 31.6 mmol) in DMSO (50 mL) wasstirred and heated at 60° C. for 2 h. After cooling, the reactionmixture was poured onto ice-cooled water (300 mL) and the precipitatedsolid was collected by filtration, then dried under reduced pressure togive the title compound. LCMS (method H): rt=1.74, [M+H]⁺=531.

Intermediate 78 Methyl2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

A solution/suspension of methyl 5-iodo-2-methoxybenzoate (20 g, 68.5mmol), bis(pinacolato)diboron (17.39 g, 68.5 mmol), potassium acetate(20.16 g, 205 mmol) and bis(triphenylphosphine)palladium(II) chloride(3.85 g, 5.48 mmol) in 1,4-dioxane (200 mL) was heated to 100° C. undernitrogen. The reaction mixture was stirred at 100° C. for 20 h and thenallowed to cool. The reaction mixture was filtered through a pad ofCELITE. The pad was washed with ethyl acetate (250 mL). To the filtratewas added 1 M hydrochloric acid (250 mL). The organic phase was washedwith brine (100 mL) and then dried over magnesium sulphate. The solventwas removed in vacuo. This was dissolved in DCM and applied to a silicacartridge (750 g) and eluted with a gradient of 0-50% ethyl acetate incyclohexane over 9 CV. The required fractions were combined andevaporated in vacuo to give the title compound. LCMS (method J):rt=1.16, [M+H]⁺=293.

Intermediate 79 and Intermediate 80 Ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propanoateand ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-2-methylpropanoate

In a dried vial, ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)acetate(Intermediate 77, 400 mg, 0.754 mmol) was stirred in THE (4.0 mL) undernitrogen at 0° C. methyl iodide (0.05 mL, 0.8 mmol) was added and themixture stirred at 0° C. for 1 min after which LiHMDS (1M in THF) (1.6mL, 1.6 mmol) was added. The reaction was stirred at 0° C. for 5 min,then allowed to warm to room temperature. After 15 minutes the reactionmixture was diluted with sat. aq. NH₄Cl (2 mL) and stirred for 5 min.The mixture was transferred to a separating funnel with DCM (20 mL) andwater (20 mL). The phases were partitioned and the organic layercollected. The aqueous was further washed with DCM (2×10 mL) and thecombined organic layers were washed with brine (20 mL), filtered througha hydrophobic frit and evaporated to dryness. The crude was wet loadedfrom DCM (1 mL) onto a 28 g KP—NH column and eluted with 10-50% withethyl acetate:ethanol (3:1, containing 1% triethylamine) in cyclohexane.The sample was further purified by reverse phase chromatography elutingwith 40-90% acetonitrile in pH10 buffered ammonium carbonate water. Thefractions containing each product were combined separately, concentratedunder reduced pressure and dried in a vacuum oven over the weekend toafford the desired title compounds. Intermediate 79: LCMS (method F):rt=1.16, [M+H]⁺=545.

Intermediate 80: LCMS (method F): rt=1.27, [M+H]⁺=559.

Intermediate 812-(3-Iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol

Ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propanoate(intermediate 79, 87 mg, 0.160 mmol) was stirred in THE (1.5 mL) at 0°C. under nitrogen. DIBAL-H (1 M in THF) (0.5 mL, 0.5 mmol) was addeddropwise and the mixture stirred for 45 min. The mixture was quenchedwith aqueous 1 M Rochelle's salt and stirred vigorously for 30 min. Themixture was separated with DCM (10 mL) and water (10 mL). The separatedaqueous phase was washed further with DCM (2×10 mL) and the combinedorganics passed through a hydrophobic frit and concentrated underreduced pressure to give the title compound. LCMS (method F): rt=0.99,[M+H]⁺=503.

Intermediate 822-(3-Iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-2-methylpropan-1-ol

Prepared in a similar manner to Intermediate 81, using ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-2-methylpropanoate(intermediate 80) to give the title compound. LCMS (method F): rt=1.12,[M+H]⁺=517.

Intermediate 83(5-Bromo-2-methoxyphenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone

Prepared in a similar manner to intermediate 29, using5-bromo-2-methoxybenzoic acid and pyrrolidin-2-ylmethanol in THF, togive the title compound. LCMS (method F): rt=0.84, [M+H]⁺=314.

Intermediate 84(2-(Hydroxymethyl)pyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone

Prepared in a similar manner to intermediate 36, using intermediate 83,to give the title compound. LCMS (method F): rt=0.96, [M+H]⁺=362.

Intermediate 85(R)-5-Bromo-N-(1-hydroxypropan-2-yl)-N,2-dimethylbenzamide

Prepared in a similar manner to intermediate 29, using5-bromo-2-methoxybenzoic acid and (R)-2-(methylamino)propan-1-ol in THF,to give the title compound. LCMS (method F): rt=0.82, [M+H]⁺=286.

Intermediate 86(R)—N-(1-Hydroxypropan-2-yl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 36, using intermediate 85,to give the title compound. LCMS (method F): rt=0.91, [M+H]⁺=334.

Intermediate 87 5-Bromo-N-(1-hydroxypropan-2-yl)-N,2-dimethylbenzamide

Prepared in a similar manner to intermediate 29, using5-bromo-2-methylbenzoic acid and 2-(methylamino)propan-1-ol in THE togive the title compound. LCMS (method F): rt=0.82, [M+H]⁺=286.

Intermediate 88N-(1-Hydroxypropan-2-yl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 36, using5-bromo-N-(1-hydroxypropan-2-yl)-N,2-dimethylbenzamide (intermediate 87)to give the title compound. LCMS (method F): rt=0.91, [M+H]⁺=334.

Intermediate 89(5-Bromo-2-methylphenyl)(3-hydroxypyrrolidin-1-yl)methanone

Prepared in a similar manner to intermediate 29, using5-bromo-2-methylbenzoic acid and pyrrolidin-3-ol in THE to give thetitle compound. LCMS (method F): rt=0.75, [M+H]⁺=284.

Intermediate 90(3-Hydroxypyrrolidin1-yl)(2-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)methanone

Prepared in a similar manner to intermediate 36, using(5-bromo-2-methylphenyl)(3-hydroxypyrrolidin-1-yl)methanone(Intermediate 89) to give the title compound. LCMS (method F): rt=0.84,[M+H]⁺=332.

Intermediate 915-Bromo-N-(1-hydroxypropan-2-yl)-2-methoxy-N-methylbenzamide

Prepared in a similar manner to intermediate 29, using5-bromo-2-methoxybenzoic acid and 2-(methylamino)propan-1-ol in THE togive the title compound. LCMS (method F): rt=0.76, [M+H]⁺=302.

Intermediate 92N-(1-Hydroxypropan2-yl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 36, using5-Bromo-N-(1-hydroxypropan-2-yl)-2-methoxy-N-methylbenzamide(intermediate 91) to give the title compound. LCMS (method F): rt=0.89,[M+H]⁺=350.

Intermediate 93 and Intermediate 94 tert-Butyl(5-(1-hydroxyethyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate,isomer 1 and isomer 2

tert-Butyl(5-(1-hydroxyethyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(intermediate 26, 60 mg, 0.123 mmol) was separated using a ChiralpakAD-H (30 mm×250 mm, 5 μm) and a solvent system of 30% ethanol(containing 0.2% isopropylamine)/heptane (containing 0.2%isopropylamine) at 30 mL/min to give the chiral title compounds. Isomer1: LCMS (method F): rt=0.97, [M+H]⁺=489. Chiral HPLC: rt 10.73, 99.7%.Isomer 2: LCMS (method F): rt=0.97, [M+H]⁺=489. Chiral HPLC: rt 7.53,100%.

Intermediate 955-Bromo-N,2-dimethyl-N-(tetrahydro-2H-pyran-4-yl)benzamide

Prepared in a similar manner to intermediate 33, using5-bromo-2-methylbenzoic acid and N-methyltetrahydro-2H-pyran-4-amine inTHE to give the title compound. LCMS (method F): rt=0.96, [M+H]⁺=312.

Intermediate 96N,2-Dimethyl-N-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Prepared in a similar manner to intermediate 32, using5-bromo-N,2-dimethyl-N-(tetrahydro-2H-pyran-4-yl)benzamide (Intermediate95) to give the title compound. LCMS (method F): rt=1.06, [M+H]⁺=360.

Intermediate 97 2-Methylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione

5-Methyl-1H-pyrazol-3-amine (50 g, 515 mmol) was dissolved in ethanol(500 mL) under nitrogen atmosphere. Sodium ethanolate (334 g, 1030 mmol)in ethanol was added followed by diethyl malonate (86 mL, 566 mmol). Thereaction mixture was stirred at 80° C. for 4 h. The reaction mixture wasallowed to cooled to room temp., and the precipitated solid wascollected by filtration, washed with excess of ethanol (1000 mL) anddried to afford the title compound. LCMS (method B): rt=0.48,[M+H]⁺=166.

Intermediate 98 5,7-Dichloro-2-methylpyrazolo[1,5-a]pyrimidine

2-Methylpyrazolo[1,5-a]pyrimidine-5,7(4H,6H)-dione (intermediate 97, 35g, 212 mmol) was added to phosphorus oxychloride (395 ml, 4239 mmol) andthe mixture was heated at 100° C. for 24 h. The mixture was cooled toroom temp. and excess phosphorus oxychloride was distilled under reducedpressure. The mixture was co-distilled with toluene (2×200 mL). Thecrude product was purified by silica gel column chromatography (20%ethyl acetate in pet. ether) to afford the title compound. LCMS (methodB): rt=3.21, [M+H]⁺=201.

Intermediate 99 5,7-Dichloro-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine

To a stirred solution of 5,7-dichloro-2-methylpyrazolo[1,5-a]pyrimidine(intermediate 98, 15 g, 74.2 mmol) in DCM (200 mL) at 0° C. was addedacetic acid (29.8 mL, 520 mmol) followed by NIS (16.70 g, 74.2 mmol)portion wise. The resulting reaction mixture was stirred at 0° C. for 1h. 10% Aqueous sodium sulphite solution (200 mL) was added andvigorously stirred at room temp. for 30 min. The DCM layer was separatedand washed with saturated sodium thiosulphate (300 mL), brine (200 mL),followed by water (100 mL) and the organic layer was dried overanhydrous sodium sulphate and filtered. The filtrate was concentratedunder reduced pressure to afford the title compound. LCMS (method E):rt=2.37, [M+H]⁺=328.

Intermediate 1005-Chloro-3-iodo-2-methyl-N-(3-(1-methyl-1H-imidazol-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine

A mixture of (3-(1-methyl-1H-imidazol-2-yl)phenyl)methylamine(intermediate 3, 31 g, 122 mmol),5,7-dichloro-3-iodo-2-methylpyrazolo[1,5-a]pyrimidine (Intermediate 99,39.9 g, 122 mmol) and DIPEA (63.8 mL, 365 mmol) in DMSO (500 mL) wasstirred and heated at 50° C. for 18 h. After cooling, the reactionmixture was poured onto ice-cooled water (1500 mL). The precipitatedsolid was collected by filtration, dried under reduced pressure toafford the title compound. LCMS (method C): rt=2.19, [M+H]⁺=479.

Intermediate 101 tert-Butyl(5-chloro-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate

To a stirred solution of5-chloro-3-iodo-2-methyl-N-(3-(1-methyl-1H-imidazol-2-yl)benzyl)pyrazolo[1,5-a]pyrimidin-7-amine(intermediate 100, 50 g, 96 mmol) in DCM (1000 mL) was added DIPEA(25.03 mL, 143 mmol), DMAP (1.167 g, 9.55 mmol) and di-tert-butyldicarbonate (33.3 mL, 143 mmol). The reaction was stirred at room temp.for 3 h. The reaction mixture was diluted with DCM (1000 mL), washedwith water (1000 mL), dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography (80% ethyl acetate in pet. ether) to affordthe title compound. LCMS (method D): rt=6.33, [M+H]⁺=579.

Intermediate 102 tert-Butyl(5-chloro-3-(3-((2-hydroxyethyl)sulfonyl)-4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate

tert-Butyl(5-chloro-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(intermediate 101, 506 mg, 0.874 mmol),2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethan-1-ol(intermediate 19, 268 mg, 0.783 mmol), triphenylarsine (13 mg, 0.042mmol), PdCl₂(PhCN)₂ (18 mg, 0.047 mmol) and sodium carbonate (193 mg,1.821 mmol) were combined in 1,4-dioxane (6 mL) and water (1.5 mL). Themixture was sparged with nitrogen for 1 min and the heated to 80° C. for4 h.2-((2-Methoxy-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethan-1-ol(intermediate 19, 113 mg, 0.330 mmol), triphenylarsine (13 mg, 0.042mmol) and PdCl₂(PhCN)₂ (18 mg, 0.047 mmol) were added. The mixture wassparged with nitrogen for 1 min and then heated to 80° C. overnight. Themixture was allowed to cool and concentrated under reduced pressure. Theresidue was slurried in ethyl acetate (20 mL) and filtered throughCELITE, washing with ethyl acetate (40 mL) and then DCM (40 mL). Thecombined filtrate was concentrated under reduced pressure to remove theDCM and then partitioned with water (40 mL). The organic phase wasseparated, passed through a hydrophobic frit and concentrated underreduced pressure. The residue was dissolved in DMSO:methanol (6 mL, 1:1)and purified by MDAP (method A). Fractions containing product werecombined and concentrated under reduced pressure to give the titlecompound. LCMS (method F): rt=1.12, [M+H]⁺=667.

Intermediate 103 Ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)butanoate

Prepared in a similar manner to Intermediate 79, using iodoethane, togive the title compound. LCMS (method F): rt=1.24, [M+H]⁺=559.

Intermediate 1042-(3-Iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)butan-1-ol

Prepared in a similar manner to intermediate 81, using ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)butanoate(intermediate 103), to give the title compound. LCMS (method F):rt=1.05, [M+H]⁺=517.

Intermediate 1053-(3-Bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)pentan-3-ol

Ethyl3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 42, 253 mg, 0.539 mmol) was stirred in THF (5 mL) at 0° C.under nitrogen. Ethylmagnesium bromide (1 M in THF) (2.4 mL, 2.4 mmol)was added over 5 min and the mixture stirred at 0° C. for 30 min thenwarmed to room temp. After 2 h, the reaction mixture was quenched withaqueous saturated ammonium chloride (2 mL) and partitioned with DCM (10mL) and aqueous saturated ammonium chloride (10 mL). The organic phasewas collected and the aqueous washed with DCM (2×5 mL). The combinedorganic layers were passed through a hydrophobic frit and evaporated todryness. The residue was stirred in THF (5 mL) under nitrogen at 0° C.Ethylmagnesium bromide (1 M in THF) (1.6 mL, 1.6 mmol) was added over 5min and the mixture stirred at 0° C. for 30 min. The mixture wasquenched with aqueous saturated ammonium chloride (2 mL) and partitionedwith DCM (10 mL) and aqueous saturated ammonium chloride (10 mL). Theorganic phase was collected and the aqueous washed with DCM (2×5 mL).The combined organic layers were passed through a hydrophobic frit andconcentrated under reduced pressure. The residue was dissolved inmethanol:DMSO (2 mL, 1:1) and purified by MDAP (method A). The fractionscontaining product were combined, evaporated to dryness and furtherdried in a vacuum oven overnight to give the title compound. LCMS(method J): rt=0.80, [M+H]⁺=483.

Intermediate 1063-Bromo-N-methoxy-N,2-dimethyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxamide

A suspension of N,O-dimethylhydroxylamine hydrochloride (1.62 g, 16.61mmol) in THF (10 mL) was cooled to −10° C.). n-Butyllithium (2.5 M inhexanes) (13 mL, 32.5 mmol) was added dropwise over 40 min to maintainthe reaction temperature below 5° C. The mixture was then stirred in theice bath for 15 min. To this solution was added slowly ethyl3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxylate(intermediate 42, 1.5 g, 3.2 mmol) in THF (10 mL). The temperature ofthe mixture was maintained below 0° C. during the addition. Once theaddition was complete, the mixture was stirred in the ice bath (at −8°C.) for 20 min and then allowed to warm to room temp. and stirred for 1h. Sat. aq. ammonium chloride (20 mL) was added and the mixture stirredfor 30 min. DCM (50 mL) was added. The solution was sonicated andtransferred to a separating funnel. The solid remaining was suspended ina mixture of water (50 mL) and DCM (50 mL) and sonicated. The mixturewas added to the separating funnel. The organic was separated and theaqueous extracted further with DCM (100 mL×2). The combined organicswere passed through a hydrophobic frit and concentrated under reducedpressure. The residue was dissolved in DCM and purified by silicachromatography eluting with 30-100% ethyl acetate:ethanol (3:1, v/v,containing 1% triethylamine) in cyclohexane over 10 CV. The fractionscontaining product were combined and concentrated under reduced pressureto give the title compound. LCMS (method J): rt=0.63, [M+H]⁺=484.

Intermediate 1071-(3-Bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-one

3-Bromo-N-methoxy-N,2-dimethyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carboxamide(Intermediate 106, 530 mg, 1.094 mmol) was dissolved in THE (20 mL) andcooled to 0° C. Ethylmagnesium bromide (1 M in THF) (2.7 mL, 2.7 mmol)was added slowly. After 20 min the mixture was quenched with saturatedaqueous ammonium chloride (5 mL) and stirred vigorously for 10 min. Theslurry was partitioned between water (50 mL) and DCM (50 mL). Theseparated aqueous phase was washed with further DCM (2×50 mL) and thecombined organics passed through a hydrophobic frit and concentratedunder reduced pressure. The residue was purified by reverse phasechromatography (C₁₈, 60 g) eluting with 30-85% acetonitrile in 10 mMammonium bicarbonate in water (adjusted to pH 10 with ammonia solution)over 25 CV. The fractions containing the desired product were combinedand concentrated under reduced pressure. The residue was purified byreverse phase chromatography (C₁₈, 40 g) eluting with 20-50%acetonitrile in water (containing 0.1% formic acid). The fractionscontaining the product were combined and neutralised using sat. aq.sodium bicarbonate, then extracted with DCM (2×50 mL). The combinedorganics were passed through a hydrophobic frit and dried under reducedpressure to give the title compound. LCMS (method J): rt=0.84,[M+H]⁺=453.

Intermediate 108 and 1091-(3-Bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 1 and isomer 2

1-(3-Bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-one(Intermediate 107, 164 mg, 0.362 mmol) was stirred in THE (3 mL) at 0°C. under nitrogen. DIBAL-H (1 M in THF) (0.75 mL, 0.75 mmol) was addeddropwise and the mixture stirred for 90 min. The mixture was quenchedwith aqueous potassium sodium tartrate (1 M) and stirred vigorously for1 h. The mixture was separated with DCM (20 mL) and water (20 mL). Theseparated aqueous phase was washed further with DCM (2×20 mL) and thecombined organics were passed through a hydrophobic frit andconcentrated under reduced pressure. The residue was purified by reversephase chromatography (C₁₈, 30 g) eluting with 10-40% acetonitrile(containing 0.1% formic acid) in water (containing 0.1% formic acid)over 10 CV. The fractions containing the product were combined andbasified using saturated aqueous sodium bicarbonate then extracted usingDCM (2×50 mL). The combined organic layers were passed through ahydrophobic frit and concentrated under reduced pressure. The residuewas purified using a Chiralpak AD-H column (30 mm×250 mm, 5 μm), elutingwith 30% ethanol (containing 0.2% isopropylamine) in hexane (containing0.2% isopropylamine) to give title compounds. Isomer 1: LCMS (method J):rt=0.61, [M+H]⁺=455. Chiral HPLC, rt 5.95, 100%. Isomer 2: LCMS (methodJ): rt=0.61, [M+H]⁺=455. Chiral HPLC, rt 9.02, 100%.

Intermediate 1101-(3-Bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one

Prepared in a similar manner to Intermediate 107, using methylmagnesiumbromide, to give the title compound. LCMS (method J): rt=0.73,[M+H]⁺=439.

Intermediate 111 and 1121-(3-Bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol,isomer 1 and isomer 2

Prepared in a similar manner to intermediate 108 and 109, to give thetitle compounds. Isomer 1: LCMS (method F): rt=0.95, [M+H]⁺=441. ChiralHPLC, rt 7.37, 100%. Isomer 2: LCMS (method F): rt=0.95, [M+H]⁺=441.Chiral HPLC, rt 11.07, 99.4%.

Intermediate 113 tert-Butyl(5-acetyl-3-bromo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate

1-(3-Bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-one(intermediate 110, 358 mg, 0.815 mmol) was suspended in THE (10 mL).DIPEA (0.21 mL, 1.202 mmol) and DMAP (10 mg, 0.082 mmol) were addedfollowed by Boc-anhydride (0.28 mL, 1.206 mmol). The mixture was stirredand heated to 50° C. for 1.5 h. The reaction was cooled to ambienttemp., diluted with water (25 mL) and ethyl acetate (25 mL). The organicphase was collected and the aqueous further washed with ethyl acetate(2×25 mL). The combined organics were passed through a hydrophobic fritand evaporated to dryness. The residue was dissolved in the minimum ofDCM (1.5 mL) and wet loaded onto a 40 g silica gel column. The productwas eluted with 0-50% ethanol:ethyl acetate (3:1, v/v, containing 1%triethylamine) in cyclohexane. Fractions containing product werecombined and evaporated to dryness, then dried under high vacuum for 2days to give the title compound. LCMS (method F): rt=1.35, [M+H]⁺=539.

Intermediate 114 tert-Butyl(3-bromo-5-(1-((tert-butyldimethylsilyl)oxy)vinyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate

tert-Butyl(5-acetyl-3-bromo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(intermediate 113, 456 mg, 0.676 mmol) was stirred in DCM (5 mL) andtriethylamine (0.32 mL, 2.296 mmol) at 0° C. under nitrogen. TBS-OTf(0.21 mL, 0.914 mmol) was added and the mixture allowed to warm toambient temp. where it was stirred for 4 h. Additional triethylamine(0.3 mL, 2.152 mmol) then TBS-OTf (0.25 mL, 1.089 mmol) were added andthe mixture was left overnight. The mixture was partitioned between DCM(20 mL) and water (20 mL). The separated aqueous phase was washed withDCM (2×10 mL) and the combined organics passed through a hydrophobicfrit and concentrated under reduced pressure. The residue was purifiedby silica chromatography eluting with 0-50% ethyl acetate incyclohexane. The residue was triturated with DCM and dried under highvacuum for 2 days to give the title compound. LCMS (method F): rt=1.70,[M+H]⁺=653.

Intermediate 115 tert-Butyl(3-bromo-5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate

Diethylzinc (1 M in heptane) (0.795 mL, 0.795 mmol) was stirred in DCM(0.5 mL) at 0° C. under nitrogen. TFA (0.061 mL, 0.795 mmol) in DCM (0.5mL) was added very slowly dropwise and the mixture stirred for 10 min.Diiodomethane (0.064 mL, 0.795 mmol) in DCM (0.5 mL) was added dropwise.After 5 minutes of stirring tert-butyl(3-bromo-5-(1-((tert-butyldimethylsilyl)oxy)vinyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(Intermediate 114, 260 mg, 0.398 mmol) in DCM (2 mL) was added. After 1h the mixture was allowed to warm to ambient temp. After 6 h sat. aq.ammonium chloride (1 mL) was added and the mixture stirred vigorouslyfor 30 min. Sat. aq. sodium bicarbonate (2 mL) was added and the mixturestirred for a further 30 min. The mixture was partitioned between DCM(20 mL) and sat. aq. ammonium chloride (20 mL). The separated aqueousphase was washed with DCM (2×10 mL) and the combined organics passedthrough a hydrophobic frit and concentrated under reduced pressure. Thecrude material was combined with the crude material from a similarreaction performed on tert-butyl(3-bromo-5-(1-((tert-butyldimethylsilyl)oxy)vinyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(intermediate 114, 51 mg, 0.078 mmol) and purified by MDAP (method A).The fractions containing product were combined, concentrated underreduced pressure and dried under high vacuum to give the title compound.LCMS (method F): rt=1.72, [M+H]⁺=667.

Intermediate 116 Methyl2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

Methyl 5-bromo-2-methylbenzoate (50 g, 218 mmol), bis(pinacolato)diboron(55.4 g, 218 mmol), potassium acetate (64.3 g, 655 mmol) andbis(triphenylphosphine)palladium(II) chloride (12.26 g, 17.46 mmol) in1,4-dioxane (500 mL) were heated to 100° C. under nitrogen for 2 h.After cooling, the mixture was filtered CELITE and washed with ethylacetate (500 mL). 1 M aqueous hydrochloric acid (500 mL) was added tothe filtrate and the phases partitioned. The organic phase was washedwith 1 M aqueous hydrochloric acid (250 mL), brine (250 mL), dried overmagnesium sulphate and the solvent removed in vacuo. The crude wassubject to purification by silica gel column chromatography eluting with0-50% ethyl acetate in cyclohexane to give the title compound. LCMS(method J): rt=1.34, [M+H]⁺=277.

Intermediate 117 Methyl5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzoate

2-(3-Bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol(intermediate 43, 25.77 g, 56.6 mmol), methyl2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate(intermediate 116, 23.44 g, 85 mmol), potassium phosphate (18.02 g, 85mmol), XPhos (2.70 g, 5.66 mmol) and XPhos Pd G2 (4.45 g, 5.66 mmol)were combined in 1,4-dioxane (300 mL) and water (100 mL). The mixturewas cycled between vacuum and nitrogen three times and then stirred andheated to 100° C. for 2 h. After cooling, the mixture was partitionedbetween ethyl acetate (250 mL) and 2 M aqueous hydrochloric acid (250mL). The separated organic phase was washed with 2 M aqueoushydrochloric acid (250 mL). The combined aqueous phases were basifiedwith 1 M aqueous sodium hydroxide solution to ˜pH 10 and extracted withethyl acetate (2×250 mL). The organics were washed with brine (100 mL),dried over magnesium sulphate and concentrated under reduced pressure togive the title compound. LCMS (method J): rt=0.78, [M+H]⁺=525.

Intermediate 1185-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzoicacid

Methyl5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzoate(intermediate 117, 32.66 g, 62.3 mmol) was stirred in methanol (300 mL).10 M aqueous sodium hydroxide (31.1 mL, 311 mmol) was added and thereaction mixture stirred at 50° C. for 6 h. After cooling, ethyl acetate(500 mL) and water (500 mL) were added and the phases partitioned. Theorganic phase was washed with 1 M aqueous sodium hydroxide (2×100 mL).The combined aqueous phases were neutralised to ˜pH 5-6 using 2 Maqueous hydrochloric acid and extracted with ethyl acetate (4×500 mL).The combined organic layers were concentrated under reduced pressure togive the title compound. LCMS (method J): rt=0.65, [M+H]⁺=511.

Intermediate 119 Methyl5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxybenzoate

2-(3-Bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol(intermediate 43, 10 g, 21.96 mmol), methyl2-methoxy-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzoate(intermediate 78, 9.62 g, 32.9 mmol), potassium phosphate (6.99 g, 32.9mmol), XPhos (1.047 g, 2.196 mmol) and XPhos Pd G2 (1.728 g, 2.196 mmol)in 1,4-dioxane (100 mL) and water (33.3 mL) was degassed(vacuum/nitrogen ×3). The reaction mixture was stirred under nitrogen at100° C. for 2 h. The reaction mixture was allowed to cool and wasseparated between ethyl acetate (250 mL) and 2 M hydrochloric acid (200mL). The organic phase was washed with 2 M hydrochloric acid (100 mL).The combined aqueous phases were basified with 1 M aqueous sodiumhydroxide solution to pH ˜10 and extracted with ethyl acetate (250 mL).The organic phase was washed with brine and dried over magnesiumsulphate. The solvent was evaporated in vacuo to give the titlecompound. LCMS (method J): rt=0.63, [M+H]⁺=541.

Intermediate 1205-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxybenzoicacid

To a solution of methyl5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxybenzoate(intermediate 119, 13.55 g, 25.06 mmol) in methanol (100 mL) was added 1M sodium hydroxide aqueous solution (12.53 mL, 125 mmol) and thereaction mixture was stirred at 50° C. for 6 h. The reaction mixture wasallowed to cool then diluted with ethyl acetate (200 mL) and water (200mL) and then filtered. The phases were separated. The aqueous phase wasneutralised to pH ˜5-6 using 2 M hydrochloric acid and then extractedusing ethyl acetate (3 times). To the aqueous phase was added solidsodium chloride. This was extracted with ethyl acetate (2×150 mL). Thecombined ethyl acetate extractions were dried over magnesium sulphate.The solvent was evaporated in vacuo to give the title compound. LCMS(method J): rt=0.57, [M+H]⁺=527.

Intermediate 121 Ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)acetate

In a dried vial ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)acetate(intermediate 77, 255 mg, 0.481 mmol) was stirred in THE (2 mL) undernitrogen at 0° C. 4-Iodotetrahydro-2H-pyran (0.06 mL, 0.503 mmol) wasadded and the mixture stirred at 0° C. for 1 min after which LiHMDS (1 Min THF) (1 mL, 1 mmol) was added. The reaction was stirred at 0° C. for10 min, then allowed to warm to room temperature and then heated to 40°C. for 2 days. The reaction mixture was diluted with sat. aq. ammoniumchloride (3 mL) and stirred for 5 min. The slurry was transferred to aseparating funnel with DCM (20 mL) and water (20 mL). The phases werepartitioned and the organic layer collected. The aqueous was furtherwashed with DCM (20 mL) and the combined organic layers washed withbrine (20 mL), then filtered through a hydrophobic frit and evaporatedto dryness. The residue was loaded from DCM (1 mL) onto a silica gelcolumn (40 g) and eluted with 10-60% ethanol:ethyl acetate (3:1, v/v,containing 1% triethylamine) in cyclohexane. The fractions containingproduct were combined and evaporated to dryness to give the titlecompound. LCMS (method F): rt=1.14, [M+H]⁺=615.

Intermediate 1223-iodo-2-methyl-N-(3-(1-methyl-1H-imidazol-2-yl)benzyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine

Ethyl2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)acetate(Intermediate 121, 158 mg, 0.188 mmol) was dissolved in THE (2 mL) and 2M sodium hydroxide (aq.) (1 mL, 2 mmol) and heated to 110° C. in asealed tube for 6 h. After cooling, DCM (20 mL) and water (20 mL) wereadded and the aqueous neutralised to pH 7 with 2 M aq. HCl. The phaseswere partitioned and the organic layer collected. The aqueous wasfurther washed with DCM (2×10 mL) and the combined organic layers passedthrough a hydrophobic frit and evaporated to dryness to give the titlecompound. LCMS (method F): rt=1.07, [M+H]⁺=543.

Intermediate 123N-(3-hydroxypropyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (245 mg,0.988 mmol) and HATU (413 mg, 1.086 mmol) and DIPEA (0.35 mL, 2.004mmol) were stirred in THE (5 mL) under air at ambient temperature. After10 minutes 3-(methylamino)propan-1-ol (0.12 mL, 1.234 mmol) was addedand the mixture stirred overnight. The mixture was partitioned betweenaqueous saturated sodium bicarbonate (30 mL) and ethyl acetate (20 mL).The separated aqueous phase was washed with further ethyl acetate (2×20mL) and the combined organics washed with brine (20 mL). The organiclayer was passed through a hydrophobic frit and concentrated underreduced pressure. The crude was purified by silica gel columnchomatography eluting with 40-100% ethyl acetate:ethanol (3:1 containing1% triethylamine) in cyclohexane to afford the title compound. LCMS(method J): rt=0.93, [M+H]⁺=320.

Supporting Compounds Compound 11-(3-(4-Methoxy-3-(methylsulfonyl)phenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethanol

3-(4-Methoxy-3-(methylsulfonyl)phenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidine-5-carbaldehyde(intermediate 12, 30 mg, 0.057 mmol) was dissolved in THE (2.5 mL) andcooled to 0° C. Methylmagnesium bromide (3 M in diethyl ether) (0.1 mL,0.3 mmol) was added dropwise and the reaction allowed to warm to roomtemp. and stirred for a further 3 h. Further methylmagnesium bromide (3M in diethyl ether) (0.1 mL, 0.3 mmol) was added and the reactionstirred for a further 20 h. The reaction was quenched by the addition of1 M HCl (10 mL), and then extracted with ethyl acetate (3×10 mL). Thecombined organic phases were dried through a hydrophobic frit and thesolvent removed in vacuo. The residue was purified by MDAP (method A) togive the title compound. LCMS (method F): rt=0.94, [M+H]⁺=547.

Compound 22-((5-(5-(1-Hydroxyethyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyphenyl)sulfonyl)ethan-1-ol

tert-Butyl(5-formyl-3-(3-((2-hydroxyethyl)sulfonyl)-4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(intermediate 20, 100 mg, 0.151 mmol) in THF (3 mL) was stirred at 0° C.under nitrogen when 3.4 M methylmagnesium bromide in 2-MeTHF (0.1 mL)was added in one portion. The reaction mixture was allowed to cool toroom temp. and the reaction was stirred under nitrogen for 1 h. Thereaction mixture was quenched with water (10 mL) and stirred undernitrogen for 5 min. The solvent was removed in vacuo. The crude materialwas dissolved in DCM (20 mL) and partitioned with water (15 mL). Theorganic layer was separated and the aqueous extracted with further DCM(2×20 mL). The combined organic layers were passed through a hydrophobicfrit and the solvent was removed in vacuo. The crude material wasdissolved in methanol (3 mL) and 4 M HCl in 1,4-dioxane (2 mL, 8 mmol)was added. The reaction was stirred under nitrogen for 5 h. The solventwas removed in vacuo. The crude material was dissolved in methanol: DMSO(2×1 mL, 1:1, v/v) and purified by MDAP (method A) to give the titlecompound. LCMS (method F): rt=0.86, [M+H]⁺=577.

The following Compounds were made in a similar manner to the preparationof Compound 2 using the following grignard reagents:

1 M Ethylmagnesium bromide in THF,0.5 M cyclopropylmagnesium bromide in THF,1 M isopropylmagnesium bromide in THF.

Compound MDAP LCMS Number Structure method method rt [M + H]⁺ 3

B F 0.91 591 4

A E 0.9 603 5

A E 0.95 605

Compound 62-(3-(3-((2-Hydroxyethyl)sulfonyl-4-methoxyphenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol

2-((2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethan-1-ol(intermediate 19, 121 mg, 0.354 mmol), sodium carbonate (87 mg, 0.821mmol), PdCl₂(dppf) (19 mg, 0.026 mmol), water (1 mL) and2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol(intermediate 21, 136 mg, 0.271 mmol) in IPA (1 mL) were combined andheated at 120° C. in a microwave reactor for 1.5 h. The reaction mixturewas filtered through CELITE (washing with DCM) and evaporated todryness. The filtrate was then partitioned between water (20 mL) and DCM(20 mL). The organic phase was collected and the aqueous washed with DCM(2×10 mL). The combined organic layers were passed through a hydrophobicfrit and evaporated to dryness. The residue was dissolved inDMSO:methanol (2 mL) and purified by MDAP (method A) to give the titlecompound. LCMS (method F): rt=0.91, [M+H]⁺=591.

Compound 72-Chloro-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N-methylbenzamide

2-Chloro-N-(3-hydroxypropyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(intermediate 23, 105 mg, 0.297 mmol), sodium carbonate (69.6 mg, 0.657mmol), PdCl₂(dppf)-DCM (12.5 mg, 0.015 mmol), water (1 mL) and2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol(intermediate 21, 110 mg, 0.219 mmol) in IPA (1 mL) were combined andheated at 120° C. in a microwave reactor for 2 h. Further2-chloro-N-(3-hydroxypropyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(intermediate 23, 105 mg, 0.297 mmol) was added and the reaction heatedat 120° C. in a microwave reactor for 2 h. The reaction mixture wasfiltered through CELITE using DCM (20 mL). The filtrate was washed withwater (20 mL) and the aqueous was extracted with further DCM (2×20 mL).The combined organic layers were passed through a hydrophobic frit andthe solvent removed under reduced pressure. The residue was dissolved inmethanol:DMSO (0.6 mL, 1:1, v/v) and purified by MDAP (method A). Theresidue was loaded in DCM (2 mL) and passed through a silica cartridge(1 g) eluting with ethyl acetate:ethanol (3:1, v/v, containing 1%triethylamine). The residue was loaded in DCM (2 mL) and purified bysilica chromatography (4 g), eluting with ethyl acetate:ethanol (3:1,v/v, containing 1% triethylamine) in cyclohexane (0%, 2 CV; 0-100%, 5CV; 100%, 7 CV) to give the title compound. LCMS (method F): rt=0.98,[M+H]⁺=602.

Compound 8(S)-(5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyphenyl)(3-hydroxypyrrolidin-1-yl)methanone

Prepared in a similar manner to Compound 7, using(S)-(3-hydroxypyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone(intermediate 25) to give the title compound. LCMS (method F): rt=0.88,[M+H]⁺=596.

Compound 95-(5-(1-Hydroxyethyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-2-methoxy-N-methylbenzamide

N-(3-Hydroxypropyl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(intermediate 28, 80 mg, 0.160 mmol) in IPA (0.5 mL), tert-butyl(5-(1-hydroxyethyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(intermediate 26, 80 mg, 0.136 mmol), PdCl₂(dppf) (9 mg, 0.012 mmol),sodium carbonate (45 mg, 0.425 mmol) and water (0.5 mL) were combinedand heated at 120° C. for 1.5 h in a microwave reactor. The reaction wasdiluted into DCM (10 mL) and water (10 mL) and the phases partitioned.The organic layer was collected and the aqueous was further washed withDCM (2×10 mL) and the combined organics were passed through ahydrophobic frit and then evaporated to dryness. The residue wasdissolved in DMSO:methanol (1:1, v/v, 1 mL) and purified by MDAP (methodA). The fractions containing product were combined and evaporated todryness. The residue was purified by silica gel column chromatographyeluting with 50-100% ethyl acetate:ethanol (3:1, v/v, containing 1%triethylamine) in cyclohexane to give the title compound. LCMS (methodF): rt=0.87, [M+H]⁺=584.

The following Compounds were prepared in a similar manner to thepreparation of Compound 9, using the following boronic esters:

-   2-Chloro-N-(3-hydroxypropyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 23),-   N-ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 30),

Cmp MDAP LCMS Number Structure method method rt [M + H]⁺ 10

A F 0.93 588 11

B F 0.89 584

Compound 125-(5-(1-Hydroxyethyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide

tert-Butyl(5-(1-hydroxyethyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(intermediate 26, 70 mg, 0.119 mmol),2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(intermediate 34, 77 mg, 0.143 mmol), PdCl₂(dppf) (9 mg, 0.012 mmol),sodium carbonate (41 mg, 0.387 mmol), IPA (2 mL) and water (1 mL) werecombined and heated in a microwave reactor at 120° C. for 1.5 h. Thereaction mixture was filtered over CELITE, washed with methanol (100 mL)and the solvent removed in vacuo. The residue was dissolved in DCM (20mL) and partitioned with water (10 mL). The organic layer was separatedand the aqueous extracted with further DCM (2×10 mL). The combinedorganic layers were passed through a hydrophobic frit and the solventremoved in vacuo. The residue was dissolved in methanol (2 mL) and 4 MHCl in 1,4-dioxane (2 mL) was added. The reaction mixture was stirredunder nitrogen at room temp. for 5 h. The solvent was removed in vacuo.The residue was dissolved in water (15 mL), neutralised with 2 M sodiumhydroxide and partitioned with DCM (20 mL). The organic layer wasseparated and the aqueous extracted with further DCM (2×20 mL). Thecombined organic layers were passed through a hydrophobic frit and thesolvent removed in vacuo. The sample was dissolved in methanol:DMSO (1mL, 1:1, v/v) and purified by MDAP (method B). The solvent was removedin vacuo. The residue was triturated with ethyl acetate then diethylether to give the title compound. LCMS (method F): rt=0.94, [M+H]⁺=610.

The following compounds were made in a similar manner to the preparationof Compound 12, varying the organic reaction solvent between IPA or1,4-dioxane, and using the following boronic esters:

-   N-(3-Hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 36),-   (S)-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(3-hydroxypyrrolidin-1-yl)methanone    (intermediate 38),-   2-chloro-N-ethyl-N-(2-hydroxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 32),-   (S)—N-(1-hydroxypropan-2-yl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 40),

Cmp MDAP LCMS Number Structure method method rt [M + H]⁺ 13

A F 0.9 568 14

A F 0.88 586 15

B J 0.61 588 16

A F 0.88 584

Compound 175-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide

N-(3-Hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(intermediate 36, 542 mg, 0.813 mmol),2-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol(intermediate 43, 333 mg, 0.622 mmol), PdCl₂(dppf) (47 mg, 0.064 mmol),sodium carbonate (198 mg, 1.865 mmol), 1,4-dioxane (3 mL) and water (1mL) were combined and heated at 120° C. for 1.5 h in a microwavereactor.N-(3-Hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(intermediate 36, 262 mg, 0.393 mmol) and PdCl₂(dppf) (20 mg, 0.027mmol) were added and the reaction mixture was heated at 120° C. for 1.5h in a microwave reactor. The reaction was diluted into DCM (20 mL) andwater (20 mL) and the phases partitioned. The organic layer wascollected and the aqueous was further washed with DCM (2×20 mL) and thecombined organics were passed through a hydrophobic frit then evaporatedto dryness. The residue was dissolved in DMSO:methanol (4 mL) andpurified by MDAP (method A). The fractions containing product werecombined and evaporated to dryness. The residue was purified by silicagel column chromatography eluting with 20-100% ethyl acetate:ethanol(3:1, v/v, containing 1% triethylamine) in cyclohexane. The fractionscontaining product were combined, evaporated to dryness and driedfurther on a high-vacuum line over 3 days to give the title compound.LCMS (method F): rt=0.96, [M+H]⁺=582.

The following Compounds were prepared in a similar manner to thepreparation of Compound 17, using either 1,4-dioxane or IPA as reactionsolvent, and the following boronic esters:

-   (S)-(2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(3-hydroxypyrrolidin-1-yl)methanone    (intermediate 38),-   N-ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 30),-   (S)—N-(1-hydroxypropan-2-yl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 40),-   N-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 34),-   (S)—N-(1-hydroxypropan-2-yl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 45),-   2-methoxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 47),-   (R)-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(2-(hydroxymethyl)pyrrolidin-1-yl)methanone    (intermediate 49),-   (R)-(2-(hydroxymethyl)pyrrolidin-1-yl)(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone    (intermediate 51),-   N-(2-hydroxyethyl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 53),-   (3-hydroxy-3-methylpyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone    (intermediate 55),-   (2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(1,4-oxazepan-4-yl)methanone    (intermediate 57),-   (S)-(3-hydroxypyrrolidin-1-yl)(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone    (intermediate 59),-   (S)-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)(3-methylmorpholino)methanone    (intermediate 61),-   (3-hydroxy-3-methylpyrrolidin-1-yl)(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone    (intermediate 63),-   N-(3-hydroxypropyl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 28)

Cmp MDAP LCMS Number Structure method method rt [M + H]⁺ 18

A F 0.96 600 19

A F 0.95 598 20

A F 0.93 598 21

A F 0.99 624 22

A F 0.98 582 23

A F 1.0 554 24

A F 1.05 614 25

A F 1.01 594 26

A, A F 0.9 584 27

A F 0.92 610 28

A F 0.98 610 29

A F 0.92 580 30

A F 1.02 610 31

A F 0.95 594 32

A, A F 0.93 598

The following Compounds were prepared in a similar manner to thepreparation of Compound 17, using intermediate 65, and either1,4-dioxane or IPA as reaction solvent, and a temperature between 100°C. and 120° C., and the following boronic esters:

-   N-(3-Hydroxypropyl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 28),-   N-(3-hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 36),-   (R)-(2-(hydroxymethyl)pyrrolidin-1-yl)(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone    (intermediate 51).

Cmp MDAP LCMS Number Structure method method rt [M + H]⁺ 33

A F 1.03 584 34

A, B F 1.06 568 35

A F 1.11 580

The following Compound was prepared in a similar manner to thepreparation of Compound 17, using the following boronic ester:

-   (R)-(2-(hydroxymethyl)pyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone    (Intermediate 67).

Cmp MDAP LCMS Number Structure method method rt [M + H]⁺ 36

A F 0.96 610

Alternative Preparation of Compound 175-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide

5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzoicacid (Intermediate 118, 12 g, 23.5 mmol), 3-(methylamino)propan-1-ol(2.81 mL, 29.4 mmol) and DIPEA (8.21 mL, 47.0 mmol) were stirred in THE(100 mL). HATU (11.17 g, 29.4 mmol) and DMF (10 mL) were added and themixture stirred under nitrogen at room temperature for 3 h. The mixturewas separated between ethyl acetate (400 mL) and saturated aqueoussodium bicarbonate (400 mL). The aqueous phase was extracted again withethyl acetate (200 mL). The combined organic phases were washed withbrine (200 mL), dried over magnesium sulphate and concentrated underreduced pressure. The residue was subjected to silica gel columnchromatography eluting with 0-25% ethanol in ethyl acetate for 5 CV and25% ethanol in ethyl acetate for 7 CV. Fractions containing product werecombined, evaporated in vacuo and purified by the same chromatographicmethod until material was >97.5% by HPLC. The residue was trituratedwith diethyl ether and the solvent evaporated in vacuo. Ethyl acetate(40 mL) was added and the mixture stirred at room temperature for 5days. The resultant white solid was collected by filtration, washed withethyl acetate (25 mL) and dried in vacuo at 40° C. to give the titlecompound. LCMS (method M): rt=2.49, [M+H]⁺=582. δ_(H) (400 MHz, d₆-DMSO)(mixture of rotamers) 8.53 (t, J=6.5 Hz, 1H), 7.73 (s, 1H), 7.71-7.67(m, 0.75H), 7.65 (s, 0.75H), 7.61 (d, J=1.3 Hz, 0.5H), 7.59-7.54 (m,1H), 7.48-7.42 (m, 2H), 7.33-7.27 (m, 1H), 7.22 (d, J=1.0 Hz, 1H), 6.94(d, J=1.0 Hz, 1H), 6.45 (s, 1H), 5.18 (s, 1H), 4.70 (d, J=6.6 Hz, 2H),4.47 (t, J=5.3 Hz, 0.5H), 4.34 (t, J=4.9 Hz, 0.5H), 3.70 (s, 3H),3.56-3.46 (m, 2H), 3.28-3.20 (m, 2H), 3.00 (s, 1.5H), 2.82 (s, 1.5H),2.58 (s, 3H), 2.21 (app. d, J=5.1 Hz, 3H), 1.79-1.70 (m, 1H), 1.66-1.57(m, 1H), 1.39 (s, 6H) ppm. δ_(C) (151 MHz, d₆-DMSO) (mixture ofrotamers) 170.3, 170.2, 169.0, 150.3, 150.2, 146.39, 146.36, 146.3,145.4, 138.6, 137.0, 136.9, 130.8, 130.14, 130.05, 130.0, 128.6, 127.5,127.4, 126.89, 126.86, 126.81, 124.84, 124.79, 123.4, 104.72, 104.67,81.55, 81.53, 72.39, 72.38, 58.4, 58.0, 47.4, 44.4, 43.5, 36.3, 34.3,31.8, 31.0, 30.1, 30.0, 18.2, 18.1, 14.7, 14.6 ppm. HRMS (ESI) calcd.for C₃₃H₃₉N₇O₃+H⁺582.3193, found 582.3190 [M+H]⁺.

Alternative Preparation of Compound 22(S)—N-(1-Hydroxypropan-2-yl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,2-dimethylbenzamide

5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzoicacid (Intermediate 118, 7.55 g, 14.79 mmol),(S)-2-(methylamino)propan-1-ol (1.977 g, 22.18 mmol) and DIPEA (5.17 mL,29.6 mmol) were stirred in THE (50 mL). DMF (2.5 mL) and HATU (7.03 g,18.48 mmol) were added the mixture stirred under nitrogen at roomtemperature for 20 h. The mixture was partitioned between ethyl acetate(200 mL) and saturated aqueous sodium bicarbonate (200 mL). The aqueousphase was extracted using ethyl acetate (100 mL). The combined organicphases were washed with brine (100 mL), dried over magnesium sulphateand the solvent removed in vacuo. The residue was subject to KP—NHend-capped silica gel column chromatography eluting with 0-100% ethylacetate in cyclohexane. The mixture was further purified by reversephase column chromatography eluting with 5-50% acetonitrile (containingammonia) in water (10 mM ammonium bicarbonate/ammonia). The residueobtained was triturated in methanol followed by diethyl ether (50 mL) inwhich the mixture was stirred rapidly for 30 minutes. The solvent wasremoved in vacuo and the residue was dissolved in ethyl acetate (70 mL)and stirred rapidly for 24 h. The solid was collected by filtration,washed with ethyl acetate dried in vacuo at 40° C. LCMS (method M):rt=2.56, [M+H]⁺=582. δ_(H) (400 MHz, d₆-DMSO) (mixture of rotamers)8.58-8.49 (m, 1H), 7.81 (d, J=8.1 Hz, 0.3H), 7.73 (s, 1H), 7.71-7.62 (m,1H), 7.59-7.51 (m, 1.7H), 7.49-7.42 (m, 2H), 7.32-7.25 (m, 1H), 7.22 (s,1H), 6.97-6.92 (m, 1H), 6.49-6.42 (m, 1H), 5.17 (s, 1H), 4.80 (t, J=5.3Hz, 0.7H), 4.76 (t, J=5.5 Hz, 0.3H), 4.70 (d, J=6.2 Hz, 2H), 3.74-3.64(m, 3.5H), 3.64-3.57 (m, 0.5H), 3.53-3.39 (m, 1.3H), 3.29-3.23 (m,0.7H), 2.90-2.84 (m, 2H), 2.68 (s, 1H), 2.60-2.56 (m, 3H), 2.25-2.18 (m,3H), 1.41-1.35 (m, 6H), 1.10 (d, J=7.0 Hz, 1H), 1.06-1.00 (m, 2H) ppm.δ_(C) (176 MHz, d₆-DMSO, 120° C.) 170.2, 168.3, 149.8, 146.1, 146.0,145.0, 137.9, 137.2, 130.7, 130.2, 129.3, 128.0, 127.1, 126.6, 126.50,126.47, 124.5, 122.6, 104.8, 81.2, 71.8, 62.0, 44.5, 33.5, 29.5, 17.5,13.8 ppm. HRMS (ESI) calcd. for C₃₃H₃₉N₇O₃+H⁺ 582.3193, found 582.3195[M+H]⁺.

Alternative Preparation of Compound 36(R)-(2-(Hydroxymethyl)pyrrolidin-1-yl)(5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyphenyl)methanone

To a solution/suspension of5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxybenzoicacid (Intermediate 120, 3.0 g, 5.7 mmol), (R)-pyrrolidin-2-ylmethanol(0.576 g, 5.7 mmol) and DIPEA (1.990 mL, 11.39 mmol) in THE (100 mL) wasadded HATU (2.71 g, 7.12 mmol). The reaction mixture was stirred undernitrogen at room temperature for 20 h. The reaction mixture waspartitioned between ethyl acetate (200 mL) and saturated sodiumbicarbonate solution (200 mL). The organic phase was washed with brine(100 mL) and dried over magnesium sulphate. The solvent was removed invacuo. The residue was dissolved in DCM and applied to a silicacartridge (120 g) and eluted with 0-25% ethanol in ethyl acetate for 5CV and 25% ethanol in ethyl acetate for 6 CV. The required fractionswere combined and evaporated in vacuo. The residue was dissolved inDMSO:methanol (1:1 v/v) and applied to a C₁₈ cartridge (120 g),pre-conditioned to 5% acetonitrile (containing ammonia) in water (10 mMammonium bicarbonate containing ammonia). This was eluted with agradient of 5-40% acetonitrile (containing ammonia) in water (10 mMammonium bicarbonate containing ammonia). The gradient was held at 29%acetonitrile (containing ammonia) in water (10 mM ammonium bicarbonatecontaining ammonia) whilst the product eluted. The required fractionswere combined and evaporated in vacuo. The residue was triturated withdiethyl ether and the solvent evaporated. To the residue was added ethylacetate (25 mL) and methanol (1 mL). The mixture was temperature cycledfrom room temp. to 45° C. and back 6 times and then left to stir at roomtemp. for 18 h. The resultant white solid was collected by filtrationand washed with ethyl acetate (25 mL). The solid was dried in vacuo at40° C. for 20 h to give the title compound. LCMS (method J): rt=0.59,[M+H]⁺=610. δ_(H)(700 MHz, DMSO-d₆, 120° C.) 7.94 (br s, 1H), 7.75 (s,1H), 7.75-7.72 (m, 1H), 7.65 (br s, 1H), 7.58 (br d, J=7.3 Hz, 1H),7.50-7.47 (m, 1H), 7.47-7.42 (m, 1H), 7.16-7.14 (m, 1H), 7.16-7.13 (m,1H), 6.95 (s, 1H), 6.44 (s, 1H), 4.74 (s, 2H), 4.18 (br s, 1H), 3.85 (s,3H), 3.75-3.71 (m, 1H), 3.70 (s, 3H), 3.51-3.42 (m, 1H), 3.39-3.15 (m,2H), 2.56 (s, 3H), 1.96-1.71 (m, 2H), 2.04-1.68 (m, 2H), 1.44 (s, 6H)ppm. δ_(C) NMR (176 MHz, DMSO-d₆, 120° C.) 168.11, 166.71, 152.36,149.48, 146.05, 146.01, 144.77, 137.90, 130.71, 128.70, 127.90, 127.35,127.05, 126.65, 126.56, 126.44, 126.43, 125.52, 122.51, 111.87, 104.61,81.02, 71.72, 61.77, 58.17, 55.49, 47.62, 44.49, 33.51, 29.45, 26.86,23.05, 13.61 ppm. HRMS (ESI) calcd. for C₃₄H₃₉N₇O₄+H⁺610.3063, found610.3141 [M+H]⁺.

Alternative Preparation of Compound 215-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide

To a solution/suspension of5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxybenzoicacid (Intermediate 120, 2.35 g, 4.46 mmol) and DIPEA (1.6 mL, 9.16 mmol)in THE (50 mL) was added HATU (2.35 g, 6.18 mmol). The mixture wasstirred at room temperature for 10 min andN-methyltetrahydro-2H-pyran-4-amine (0.514 g, 4.46 mmol) was added. Themixture was stirred under nitrogen at room temp. for 16 h. The reactionmixture was partitioned between ethyl acetate (100 mL) and sat. aq.sodium bicarbonate solution (100 mL). The aqueous was extracted a secondtime with ethyl acetate (100 mL). The combined organic phases werewashed with brine (100 mL) and passed through a hydrophobic frit. Thesolvent was removed under reduced pressure. The residue was purified bysilica chromatography (340 g). The compound was dissolved in a minimumof DCM (+few drops of methanol), loaded onto the top of the column byinjection, then eluted using 0-25% ethanol in ethyl acetate over 6 CVand then held at 25% ethanol in ethyl acetate for 6 CV. The fractionscontaining the desired product were combined and concentrated underreduced pressure. Approximately half the material was dissolved inDMSO:methanol (1:1 v/v) and applied to a C₁₈ cartridge (120 g),pre-conditioned to 5% acetonitrile (containing ammonia) in water (10 mMammonium bicarbonate containing ammonia), then eluted with a gradient of5-20% acetonitrile (containing ammonia) in water (10 mM ammoniumbicarbonate containing ammonia) over 6 CV and then 20-60% acetonitrile(containing ammonia) in water (10 mM ammonium bicarbonate containingammonia) over 6 CV. The gradient was held at 47.5% acetonitrile(containing ammonia) in water (10 mM ammonium bicarbonate containingammonia) whilst the product eluted. The remainder of the material waspurified in a similar manner, using a gradient of 25-55% acetonitrile(containing ammonia) in water (10 mM ammonium bicarbonate containingammonia), bicarbonate/NH3). The gradient was held at 45% acetonitrile(containing ammonia) in water (10 mM ammonium bicarbonate containingammonia) whilst the product eluted. The fractions containing pureproducts from both purifications were combined, concentrated underreduced pressure, then dried under vacuum for 24 h to give the titlecompound. LCMS (method J): rt=0.65, [M+H]⁺=624. δ_(H) (600 MHz, d₆-DMSO)(mixture of rotamers) 8.54-8.49 (m, 1H), 7.77-7.72 (m, 2H), 7.63 (d,J=1.8 Hz, 0.5H), 7.59-7.54 (m, 1H), 7.53 (d, J=2.2 Hz, 0.5H), 7.47-7.43(m, 2H), 7.22 (s, 1H), 7.18-7.13 (m, 1H), 6.94 (s, 1H), 6.43 (s, 1H),5.17 (s, 1H), 4.69 (d, J=6.2 Hz, 2H), 4.64-4.58 (m, 0.5H), 3.98-3.91 (m,1H), 3.90-3.85 (m, 0.5H), 3.82-3.75 (m, 3.5H), 3.70 (s, 3H), 3.57-3.50(m, 0.5H), 3.43 (t, J=11.2 Hz, 1H), 3.12 (t, J=11.2 Hz, 0.5H), 3.00 (t,J=11.6 Hz, 0.5H), 2.88 (s, 1.5H), 2.69 (s, 1.5H), 2.56 (ap. d, J=15.8Hz, 3H), 1.89-1.72 (m, 2H), 1.59-1.51 (m, 1.5H), 1.42 (d, J=11.4 Hz,0.5H), 1.39-1.33 (m, 6H) ppm. δ_(C) (151 MHz, d₆-DMSO) (mixture ofrotamers) 168.80, 168.77, 168.1, 167.9, 152.50, 152.47, 150.0, 149.9,146.4, 146.34, 146.26, 145.18, 145.16, 138.6, 130.8, 129.2, 128.9,128.6, 127.5, 126.89, 126.87, 126.80, 126.7, 126.6, 126.5, 125.9, 123.4,111.6, 111.4, 104.7, 104.5, 81.4, 81.3, 72.4, 72.3, 66.5, 66.3, 66.2,55.7, 55.4, 54.9, 54.8, 49.4, 44.4, 34.3, 30.5, 30.3, 30.09, 30.07,30.0, 29.2, 26.6, 14.5, 14.4 ppm. HRMS (ESI) calcd. forC₃₅H₄₁N₇O₄+H⁺624.3220, found 624.3294 [M+H]⁺.

Compound 372-Chloro-N-(2-hydroxyethyl)-5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-methylbenzamide

A microwave vial was charged with2-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol(Intermediate 43, 305 mg, 0.636 mmol), XPhos (32 mg, 0.067 mmol), XPhosPd G2 (53 mg, 0.067 mmol) and tripotassium phosphate (443 mg, 2.087mmol).2-Chloro-N-(2-hydroxyethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 69), 446 mg, 0.788 mmol) was dissolved in 1,4-dioxane (7.5mL) and added to the microwave vial followed by water (2.5 mL). The vialwas sealed and heated in a microwave at 100° C. for 1.5 h. The reactionmixture was diluted with water (25 mL) and partitioned with DCM (25 mL).The organic phase was collected and the aqueous phase was washed withDCM (4×25 mL). The organic phases were combined and the solvent waspassed through a hydrophobic frit and then a second hydrophobic fritwith a layer of Florisil (2 cm deep). The Florisil layer was washed withethyl acetate:ethanol (3:1, containing 1% triethylamine) (25 mL). Thefiltrate was evaporated to dryness. The residue was dissolved in aminimum amount of DMSO:methanol (1:1, v/v) and purified by MDAP (methodA). The relevant fractions were combined and the solvent was removed.The residue was purified by silica column chromatography eluting with30-100 ethyl acetate:ethanol (3:1, containing 1% triethylamine) incyclohexane. The relevant fractions were combined and the solvent wasremoved. The residue was triturated with a minimum amount of diethylether to give the title compound. LCMS (method F): rt=0.96, [M+H]⁺=588.

The following Compounds were prepared in a similar manner to thepreparation of Compound 37, using the following boronic esters:

-   N-Ethyl-N-(2-hydroxyethyl)-2-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)benzamide    (Intermediate 73),-   (R)—N-(1-Hydroxypropan-2-yl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 86),-   N-(1-Hydroxypropan-2-yl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 88),-   (3-Hydroxypyrrolidin1-yl)(2-methyl-5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)phenyl)methanone    (intermediate 90),-   N-(1-Hydroxypropan2-yl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 92)

Cmp LCMS Number Structure method rt [M + H]⁺ 38

F 0.98 582 39

F 0.98 582 40

F 0.99 582 41

F 0.92 580 42

F 0.93 598

The following Compounds were prepared in a similar manner to thepreparation of Compound 17, and either 1,4-dioxane or IPA as reactionsolvent, and a temperature between 100° C. and 140° C., and thefollowing boronic esters:

-   N-(2-Hydroxyethyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (Intermediate 71),-   (2-(Hydroxymethyl)pyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone    (intermediate 84),-   N,2-Dimethyl-N-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (intermediate 96),

Cmp MDAP LCMS Number Structure method method rt [M + H]⁺ 43

A F 0.93 568 44

A F 0.97 610 45

A, B F 1.04 608

The following Compounds were prepared in a similar manner to thepreparation of Compound 17, using intermediate 65, and either1,4-dioxane or IPA as reaction solvent, and a temperature between 100°C. and 140° C., and the following boronic esters:

-   N-(2-hydroxyethyl)-2-methoxy-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (Intermediate 53),-   N-(2-Hydroxyethyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (Intermediate 71),-   2-Chloro-N-(2-hydroxyethyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide    (Intermediate 69),-   (R)-(2-(Hydroxymethyl)pyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan    yl)phenyl)methanone (Intermediate 67),-   (S)-(3-Hydroxypyrrolidin-1-yl)(2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone    (Intermediate 59),-   (3-Hydroxy-3-methylpyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone    (Intermediate 55),-   (S)-(3-Hydroxypyrrolidin-1-yl)(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanone    (Intermediate 25),

Cmp MDAP LCMS Number Structure method method rt [M + H]⁺ 46

A, B F 1.00 570 47

A, B F 1.04 554 48

A F 1.07 574 49

A, A F 1.08 596 50

A, B F 1.02 566 51

A F 1.02 596 52

B, B J 0.87 582

Compound 532-(3-(3-((2-Hydroxyethyl)sulfonyl)-4-methoxyphenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol

Prepared in a similar manner to compound 37 using2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol(intermediate 81) and2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethanol(Intermediate 19) to give the title compound. LCMS (method J): rt=0.53,[M+H]⁺=591.

Compound 545(5-(1-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide

Prepared in a similar manner to Compound 17, using2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol(Intermediate 81) andN-(3-hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 36) to give the title compound. LCMS (method F): rt=0.92,[M+H]⁺=582.

Compound 555-(5-(1-Hydroxy-2-methylpropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide

Prepared in a similar manner to Compound 17 using2-(3-Iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-2-methylpropan-1-ol(Intermediate 82) andN-(3-hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 36) to give the title compound. LCMS (method F): rt=0.99,[M+H]⁺=596.

Compound 562-(3-(3-((2-Hydroxyethyl)sulfonyl)-4-methoxyphenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-2-methylpropan-1-ol

Prepared in a similar manner to Compound 17 using2-(3-Iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-2-methylpropan-1-ol(intermediate 82) and2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethanol(Intermediate 19) to give the title compound. LCMS (method F): rt=0.95,[M+H]⁺=605.

Compound 572-Chloro-5-(5-(1-hydroxyethyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N-methylbenzamide,isomer

Prepared in a similar manner to Compound 37 using tert-butyl(5-(1-hydroxyethyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate,isomer 1 (Intermediate 93) and2-chloro-N-(3-hydroxypropyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 23) to give the title compound. LCMS (method F): rt=0.95,[M+H]⁺=588.

Compound 582-Chloro-5-(5-(1-hydroxyethyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N-methylbenzamide,isomer 2

Prepared in a similar manner to compound 37 using tert-butyl(5-(1-hydroxyethyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate,isomer 2 (intermediate 94) and2-chloro-N-(3-hydroxypropyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 23) to give the title compound. LCMS (method F): rt=0.95,[M+H]⁺=588.

Compound 595-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,2-dimethyl-N-(tetrahydrofuran-3-yl)benzamide

A solution of5-(5-(2-hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methylbenzoicacid (Intermediate 118, 49 mg, 0.096 mmol), HATU (40.1 mg, 0.106 mmol)and DIPEA (0.034 mL, 0.192 mmol) in DMF (0.4 mL) was stirred for 20 minat room temp. N-Methyltetrahydrofuran-3-amine (0.013 mL, 0.115 mmol) wasadded to the reaction mixture and stirred for 1 h at room temp. thenleft overnight. The reaction mixture was diluted with methanol (0.6 mL)and purified by MDAP (method A). Appropriate fractions were combined,concentrated, triturated with diethyl ether, then dried under highvacuum to give the title compound. LCMS (method F): rt=1.04, [M+H]⁺=594.

The following compounds were prepared in a similar manner to Compound59, using the following amines:

-   3-Aminopropan-1-ol,-   1-(methylamino)propan-2-ol

Cmp MDAP LCMS Number Structure method method rt [M + H]⁺ 60

A F 0.92 568 61

A J 0.6 582

Compound 62 and Compound 635-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(2-hydroxypropyl)-N,2-dimethylbenzamide,isomer 1 (Compound 62) and isomer 2 (Compound 63)

Compound 61 was purified using a Chiralpak AS-H column (30 mm×250 mm, 5μm), eluting with acetonitrile containing 0.2% isopropylamine to givethe title compounds. Isomer 1: LCMS (method F): rt=0.98, [M+H]⁺=582.Chiral HPLC: rt 6.85, 100%. Isomer 2: LCMS (method F): rt=0.98,[M+H]⁺=582. Chiral HPLC: rt 8.36, 98.5%.

Compound 642-((2-Methoxy-5-(2-methyl-7-((3-(1-methyl-1H-imidazol2-yl)benzyl)amino)-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)sulfonyl)ethan-1-ol

To a dried vial was added2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(18 mg, 0.086 mmol), Pd XPhos G2 (6 mg, 7.63 μmol), Pd/C (51 mg, 0.048mmol), tripotassium phosphate (51 mg, 0.240 mmol) and tert-butyl(5-chloro-3-(3-((2-hydroxyethyl)sulfonyl)-4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(Intermediate 102, 55 mg, 0.082 mmol). The vial was capped and purgedwith nitrogen. Water (0.2 mL) and 1,4-dioxane (0.8 mL) were added andthe mixture heated to 100° C. for 45 min. The mixture was allowed tocool to room temp. Ammonium formate (1.25 M in methanol) (0.659 mL,0.824 mmol) was added and the mixture stirred overnight. The mixture washeated to 40° C. for 6 h. The vial was purged with nitrogen and thecontents filtered through CELITE, washing with DCM (10 mL). The filtratewas partitioned with water (10 mL) and the separated aqueous phasewashed with DCM (2×10 mL). The combined organic layers were passedthrough a hydrophobic frit and concentrated under reduced pressure. Theresidue was combined with the residue from a similar reaction performedon tert-butyl(5-chloro-3-(3-((2-hydroxyethyl)sulfonyl)-4-methoxyphenyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(Intermediate 102, 20 mg, 0.03 mmol), dissolved in methanol (1.4 mL) andhydrochloric acid (3 M in CPME) (0.35 mL, 1.05 mmol) was added. Themixture was stirred overnight at room temp., then 40° C. for 7 h. Themixture was allowed to stand at room temp. over the weekend. Sat. aq.sodium bicarbonate (1 mL) was added and the mixture stirred for 5 min.DCM (2 mL) was added and the mixture partitioned. The separated aqueousphase was washed with DCM (2×1 mL) and the combined organics passedthrough a hydrophobic frit and concentrated under a stream of inert gas.The residue was dissolved in DMSO:methanol (0.5 mL, 1:1) and purified byMDAP (method A). The fractions containing product were combined,concentrated under reduced pressure and dried on the high vacuum line togive the title compound. LCMS (method F): rt=0.95, [M+H]⁺=617.

Compound 655(5-(1-Hydroxybutan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide

Prepared in a similar manner to Compound 37, using2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)butan-1-ol(Intermediate 104) andN-(3-hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 36) to give the title compound. LCMS (method F): rt=0.97,[M+H]⁺=596.

Compounds 66 and 675(5-(1-Hydroxybutan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide,isomer 1 (Compound 66) and isomer 2 (Compound 67)

Compound 65 was purified using a Chiralpak AD-H column (30 mm×250 mm, 5μm), eluting with 40% ethanol (containing 0.2% isopropylamine) inheptane (containing 0.2% isopropylamine) to give the title compounds.Isomer 1: LCMS (method J): rt=0.58, [M+H]⁺=596. Chiral HPLC: rt 9.41,100%. Isomer 2: LCMS (method J): rt=0.58, [M+H]⁺=596. Chiral HPLC: rt14.57, 99.5%.

Compound 685-(5-(3-Hydroxypentan-3-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide

Prepared in a similar manner to Compound 37, using3-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)pentan-3-ol(Intermediate 105) andN-(3-hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(intermediate 36) to give the title compound. LCMS (method J): rt=0.71,[M+H]⁺=610.

Compound 69N-(3-Hydroxypropyl)-5-(5-(1-hydroxypropyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,2-dimethylbenzamide,isomer 1

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 1 (intermediate 108) andN-(3-hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 36) to give the title compound. LCMS (method J): rt=0.65,[M+H]⁺=582.

Compound 70N-(3-Hydroxypropyl)-5-(5-(1-hydroxypropyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N,2-dimethylbenzamide,isomer 2

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 2 (Intermediate 109) andN-(3-hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 36) to give the title compound. LCMS (method J): rt=0.61,[M+H]⁺=582.

Compound 712-((5-(5-(1-Hydroxyethyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyphenyl)sulfonyl)ethan-1-ol,isomer 1

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol,isomer 1 (Intermediate 111) and2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethanol(Intermediate 19) to give the title compound. LCMS (method F): rt=0.87,[M+H]⁺=577.

Compound 722-((5-(5-(1-Hydroxyethyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxyphenyl)sulfonyl)ethan-1-ol,isomer 2

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol,isomer 2 (intermediate 112) and2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethanol(Intermediate 19) to give the title compound. LCMS (method F): rt=0.86,[M+H]⁺=577.

Compound 732-Chloro-5-(5-(1-hydroxyethyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N-methylbenzamide,isomer

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol,isomer 1 (intermediate 111) and2-chloro-N-(3-hydroxypropyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 23) to give the title compound. LCMS (method F): rt=0.93,[M+H]⁺=588.

Compound 742-Chloro-5-(5-(1-hydroxyethyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N-methylbenzamide,isomer

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethan-1-ol,isomer 2 (intermediate 112) and2-chloro-N-(3-hydroxypropyl)-N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 23) to give the title compound. LCMS (method F): rt=0.93,[M+H]⁺=588.

Compound 751-(3-(3-((2-Hydroxyethyl)sulfonyl)-4-methoxyphenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 1

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 1 (intermediate 108) and2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethanol(Intermediate 19) to give the title compound. LCMS (method F): rt=0.91,[M+H]⁺=591.

Compound 761-(3-(3-((2-Hydroxyethyl)sulfonyl)-4-methoxyphenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 2

Prepared in a similar manner to Compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 2 (Intermediate 109) and2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethanol(Intermediate 19) to give the title compound. LCMS (method F): rt=0.91,[M+H]⁺=591.

Compound 775(5-(1-Hydroxypropyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide,isomer 1

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 1 (intermediate 108) and2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 34) to give the title compound. LCMS (method J): rt=0.63,[M+H]⁺=624.

Compound 785-(5-(1-Hydroxypropyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzamide,isomer 2

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 2 (Intermediate 109) and2-methoxy-N-methyl-N-(tetrahydro-2H-pyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 34) to give the title compound. LCMS (method J): rt=0.64,[M+H]⁺=624.

Compound 795-(5-(1-Hydroxycyclopropyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N,2-dimethylbenzamide

tert-Butyl(3-bromo-5-(1-((tert-butyldimethylsilyl)oxy)cyclopropyl)-2-methylpyrazolo[1,5-a]pyrimidin-7-yl)(3-(1-methyl-1H-imidazol-2-yl)benzyl)carbamate(Intermediate 115, 26 mg, 0.039 mmol), potassium phosphate (24 mg, 0.113mmol), XPhos (2 mg, 4.20 μmol), XPhos Pd G2 (3 mg, 3.81 μmol) andN-(3-hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 36, 25 mg, 0.053 mmol) were combined in 1,4-dioxane (0.4mL) and water (0.133 mL). The mixture was heated to 60° C. in a sealedvial for 1 h 45 min. XPhos Pd G2 (3 mg, 3.81 μmol) andN-(3-hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 36, 25 mg, 0.053 mmol) were added. After 1 h, the reactiontemperature was increased to 80° C. After 2 h XPhos Pd G2 (3 mg, 3.81μmol) andN-(3-hydroxypropyl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 36, 25 mg, 0.053 mmol) were added and the mixture heatedto 100° C. for 1 h. The mixture was partitioned between water (10 mL)and ethyl acetate (10 mL). The separated aqueous phase was washed withethyl acetate (2×10 mL) and the combined organics passed through ahydrophobic frit and concentrated under reduced pressure. The residuewas dissolved in 1,4-dioxane (1.0 mL) and then HCl (4 M in 1,4-dioxane)(0.1 mL) was added. The mixture was stirred at room temperature for 4days. Saturated aqueous sodium bicarbonate (3 mL) was added and themixture stirred for 10 min. Water (10 mL) and DCM (10 mL) were added andthe phases partitioned. The separated aqueous phase was washed with DCM(2×5 mL) and the combined organic layers passed through a hydrophobicfrit and concentrated under reduced pressure. The residue was purifiedby MDAP (method A). The fractions containing desired product werecombined and concentrated under reduced pressure to give the titlecompound. LCMS (method F): rt=0.97, [M+H]⁺=580.

Compound 80N—((S)-1-Hydroxypropan-2-yl)-5-(5-(1-hydroxypropyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin3-yl)-N,2-dimethylbenzamide,isomer 1

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 1 (intermediate 108) and(S)—N-(1-hydroxypropan-2-yl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 45) to give the title compound. LCMS (method J): rt=0.62,[M+H]⁺=582.

Compound 81N—((S)-1-Hydroxypropan-2-yl)-5-(5-(1-hydroxypropyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin3-yl)-N,2-dimethylbenzamide,isomer 2

Prepared in a similar manner to compound 37 using1-(3-bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-1-ol,isomer 2 (Intermediate 109) and(S)—N-(1-hydroxypropan-2-yl)-N,2-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(intermediate 45) to give the title compound. LCMS (method J): rt=0.61,[M+H]⁺=582.

Compound 825-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(2-hydroxypropyl)-2-methoxy-N-methylbenzamide

5-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-2-methoxybenzoicacid (intermediate 120, 65 mg, 0.101 mmol), HATU (47 mg, 0.124 mmol) andDIPEA (0.055 mL, 0.315 mmol) were stirred in THE (1 mL) at roomtemperature for 5 min after which 1-(methylamino)propan-2-ol (13 mg,0.146 mmol) was added. After 2 h, additional HATU (12 mg, 0.032 mmol)and DIPEA (0.018 mL, 0.101 mmol) were added. After 1.5 hours thereaction mixture was purified by MDAP (method A). Product fractions werecombined and dried under a stream of inert gas to give the titlecompound. LCMS (method F): rt=0.96, [M+H]⁺=598.

Compounds 83 and 845-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(2-hydroxypropyl)-2-methoxy-N-methylbenzamide,isomer 1 (Compound 83) and isomer 2 (Compound 84)

Compound 82 was purified on a Chiralpak IC column (30 mm×250 mm, 5 μm),eluting with 30% ethanol (containing 0.2% isporopylamine) in heptane(containing 0.2% isporopylamine) to give the title compounds. Isomer 1:LCMS (method F): rt=0.94, [M+H]⁺=598. Chiral HPLC: rt 28.8, 100%. Isomer2: LCMS (method F): rt=0.94, [M+H]⁺=598. Chiral HPLC: rt 33.68, 96.6%.

Compound 852-((2-Methoxy-5-(2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)sulfonyl)ethan-1-ol

Prepared in a similar manner to compound 9 using3-iodo-2-methyl-N-(3-(1-methyl-1H-imidazol-2-yl)benzyl)-5-((tetrahydro-2H-pyran-4-yl)methyl)pyrazolo[1,5-a]pyrimidin-7-amine(Intermediate 122) and2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethanol(Intermediate 19) to give the title compound. LCMS (method F): rt=0.94,[M+H]⁺=631.

Compound 862-(3-(3-((2-Hydroxyethyl)sulfonyl)-4-methoxyphenyl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)butan-1-ol

Prepared in a similar manner to compound 37 using2-(3-iodo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)butan-1-ol(Intermediate 104) and2-((2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)sulfonyl)ethanol(Intermediate 19) to give the title compound. LCMS (method F): rt=0.92,[M+H]⁺=605.

Compound 873-(5-(2-Hydroxypropan-2-yl)-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)-N-(3-hydroxypropyl)-N-methylbenzamide

2-(3-Bromo-2-methyl-7-((3-(1-methyl-1H-imidazol-2-yl)benzyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)propan-2-ol(Intermediate 43, 150 mg, 0.313 mmol), potassium phosphate (165 mg,0.777 mmol),dicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphane (12mg, 0.025 mmol), XPhos Pd G2 (22 mg, 0.028 mmol) andN-(3-hydroxypropyl)-N-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(Intermediate 123, 219 mg, 0.412 mmol) were combined in a microwavevial. 1,4-Dioxane (1.8 mL) and water (0.6 mL) were added, the vialsealed and the mixture heated to 100° C. in a microwave reactor for 1 h.After cooling, the organic layer of the biphasic reaction mixture wasfiltered through cotton wool and purified directly by MDAP (method A).The residue obtained was partitioned between aqueous saturated sodiumbicarbonate (10 mL) and DCM (5 mL). The separated aqueous phase waswashed with further DCM (2×5 mL). The organics were combined, passedthrough a hydrophobic frit, concentrated under a stream of inert gas anddried under high vacuum at 40° C. for 1 day to give the title compound.LCMS (method F): rt=0.94, [M+H]⁺=568.

Biological Assays

a) PI4 KB Activity Assay

The in vitro inhibition of human PI4KIII-beta 13-828 (D316-330) activitywas determined by using the ADP-GLO Kinase assay kit from Promega.Inhibitors were dissolved in 100% DMSO at a concentration of 1 mM.Dilutions were prepared in 100% DMSO using a 1 in 3 serial stepdilution. A 60 nL stamp from an 11-point titration was transferred to awhite low volume 384 well Greiner assay plate ensuring a final DMSOconcentration of 1% across the plate and a top final concentration ofinhibitor of 10 μM. The PI4KIII-beta assay contained 25 mM Hepes pH 7.5(NaOH), 10 mM MgCl2, 0.5 mM EGTA, 0.1% Triton X-100, 2 mM TCEP, and 0.1mg/ml BSA, 1 mM ATP, 60 μM phosphatidylinositol, and 1.5 nM humanPI4K-beta 13-828 (D316-330) in a total volume of 6 μL. The assay wasinitiated with the addition of enzyme, covered, and incubated at roomtemperature for 3 hours. The assays were stopped with the addition of 6μl ADP-GLO Reagent containing 0.1% CHAPS to deplete the unconsumed ATP.The plates were incubated at room temperature for 60 min and then 12 μlof the Kinase Detection Reagent containing 0.1% CHAPS was added toconvert ADP to ATP and introduce luciferase and luciferin. After 40 minincubation at room temperature the luminescent signal was read on a BMGLabtech PHERAstar FS with the following settings; Gain 3600, Focalheight 13.7 mm, measurement interval time 1 s, Settling time 0.2 s. Theinhibitory effect of the PI4K-beta activity of the compounds wasevaluated by the IC50 of the response relative to the high, no compound,and low, no enzyme, controls by fitting to the four parameter doseresponse question.

When tested in this assay: all Compounds gave a mean pIC50 of greaterthan or equal to 8.1; compounds 1-7, 9-11, 14, 15, 17-20, 22-29 and31-87 gave a mean pIC50 of greater than or equal to 8.4; Compounds 17and 19 gave a mean pIC50 of 8.6; Compound 21 gave a mean pIC50 of 8.2;and Compound 22 gave a mean pIC50 of 8.5.

b) Residence Time Assay

Caliper Conditioning Assay

Compound dilutions were prepared in 100% DMSO using a 1 in 3 serial stepdilution and a top concentration of 1 mM. A 200 nL stamp from a 12-pointtitration was transferred to a black 384-well Greiner assay plateensuring a final DMSO concentration of 1% across the plate and a topfinal concentration of inhibitor of 10 μM in 20 μL final assay volume.To a well of a 384-well assay plate 10 μL of 2× Enzyme buffer waspre-incubated with compound for 1 h. Buffer without enzyme was used as100%-inh control. 10 μL of 2× substrate solution was added to initiatethe assay such that the final concnetrations were 2 mM ATP and 1 μMBodipy-PI and the plate was incubated at 25° C. for 3 hours. Theenzymatic reaction was terminated by adding 40 μL of stop buffer andSubstrate (PI) and product (PIP) present in each sample were separatedelectrophoretically using a LabChip 3000 capillary electrophoresisinstrument CALIPER LABCHIP 3000 Drug Discovery System and detected usingblue laser (480 nm) for excitation and green CCD (520 nm) for detection(CCD2). Negative control samples (0%-inhibition in the absence ofinhibitor) and positive control samples (100%-inhibition, in the absenceof enzyme) were assembled in replicates of 48 (4 replicates per calipersipper) and were used to calculate %-inhibition values in each testwell. Percent inhibition (Pinh) was determined using following equation:

Pinh=(PSR0%−PSRinh)/(PSR0%−PSR100%)×100

Where PSRinh is the product sum ratio in the presence of inhibitor,PSR0% is the average product sum ratio in the absence of inhibitor andPSR100% is the average product sum ratio in 100%-inhibition controlsamples; the IC50 values of inhibitors are determined by fitting theinhibition curves (Pinh versus inhibitor concentration) to the 4parameter sigmoid dose-response model using XLfit 4 software (IBDS).

Jump Dilution

In a small Eppendorf tube, 5 μL of 2× enzyme solution (0.4 μM-0.8 μM)was mixed with 5 μL 2× compound solution containing 40 to 120-fold theIC50 value determined at 2 mM ATP as described above, and incubated for1 h at room temperature. The assay was initiated by rapidly mixing 2 μLof the enzyme preincubation mixture with 800 μL substrate mix containing2 mM ATP and 1 μM Bodipy-PI. 60 μL of each sample was transferred intolow volume Greiner 384-well plate, and the Substrate (PI) and product(PIP) present in each sample were separated electrophoretically using aLabChip 3000 capillary electrophoresis instrument CALIPER LABCHIP 3000Drug Discovery System and detected using blue laser (480 nm) forexcitation and green CCD (520 nm) for detection (CCD2) for approximately8 h (200 measurements from each well). The progress curves, in %conversion against time, in the presence of compound are compared tothat in control samples without compound. The curves were fit to theprogress curve equation using XLfit software:

[P]=Vs×t+((Vi−Vs)/Kobs)×(1−exp(−Kobs×t))

Where Vi is the initial velocity of the enzyme, Vs is the steady statevelocity in the presence of diluted inhibitor, and t is the time afterdilution.

The observed Vi, Vs and Kobs values will depend on the nature ofinhibitor (i.e. rapid equilibrium versus tight binding). Depending onthe initial assay conditions (relative concentration of compound versusenzyme), Vi and Vs parameters can be pre-fitted and/or locked. For slowdissociating compounds >[E], the initial enzyme velocity (after rapiddilution) is generally not locked; Steady state velocity can be lockedto that in the presence of residual compound (derived from the IC50curve). For some rapid equilibrium compounds (1/2 residence <assayresolution) tested >[E], the initial velocity could be locked to thetheoretical %-activity derived from the IC50 curves at the correspondingcompound concentrations and the steady state velocity could bepre-fitted to control but not locked. For the remainder of rapidequilibrium or slow dissociation compounds, an alternative approach ofpreestimating but unlocking Vi and Vs to the theoretical velocitiesderived from the IC50 curves at the corresponding compoundconcentrations can be taken, for example, in cases such as when theabove strategies fail to produce appropriate fits.

In this assay, Compound 17 showed a mean residence time of 542 minutes;Compound 19 showed a mean residence time of 997 minutes; Compound 21showed a mean residence time of 528 minutes; and Compound 22 showed amean residence time of 1666 minutes.

c) Cytopathic Effect (CPE) Assay Protocol

The in vitro inhibition of PI4 KB activity was determined by analysis ofthe inhibition of ATP-depletion in HeLa Ohio cells in response toinfection with human rhinovirus Type A Strain 16 (HRVA16). ATP levelswere determined using CellTiter-GLO reagent from Promega. Compounds thatinhibit PI4 KB are also potent inhibitors of human rhinoviruses and areable to protect HeLa Ohio cells from CPE induced by viral infection andreplication. Protected cells remain viable following viral infection andtherefore have greater ATP levels.

Compounds were dissolved in 100% DMSO to a concentration of 3 mM andsubsequent dilutions were prepared in 100% DMSO using a 1:3 serial stepdilution. A 0.5 μL stamp from an 10-point titration was transferred to awhite 96 well Greiner tissue culture flat bottom plate (655083). A 0.5μL stamp of 100% DMSO was stamped into columns 11 and 12 of the plate,ensuring a final assay DMSO concentration of 0.33% across the plate anda compound top final assay concentration of 10 μM.

HeLa Ohio cells were cultured at 37° C., 5% CO2 in media (DMEMsupplemented with 10% Australian origin foetal bovine serum and 2 mMglutamax). Cells were passaged when confluency reached >80%. For theassay, cells were grown to 80-90% confluency before detachment.

Cells were detached for the assay by washing with PBS and detached using3 mL TrypLE Express for 5 mL at 37° C. Detached cells were mixed with 7mL of media and centrifuged at 300 g for 5 min. The cell pellet wasresuspended in 50 mL media and counted on a Beckman Coulter ViCell.Cells were diluted to 6.6×104 cells/mL and some of the cell volume wasremoved into a new tube to be used as a column 12 control. HRVA16 stockwas added to the remaining cell suspension at the appropriate dilutionfor the virus stock to achieve an MOI of 1.

150 μL of the cell+virus suspension was added per well to columns 1-11using a Multidrop Combi. 150 μL of the separate cell suspension wasadded per well to columns 12 using a multichannel pipette. Assay plateswere sealed and incubated at 33° C., 5% CO2 for 2 days. After 2 days,assay plates were removed from the incubator and allowed to equilibrateto room temperature. 60 μL of CellTiter-Glo reagent was added to allwells using a Thermo Scientific Multidrop Combi. Plates were incubatedat room temperature for 20 min before reading on an a Perkin ElmerEnvision (Settings: Gripper height 2.5, Fixed measurement height (mm)6.5, Distance between plate and detector 0, Measurement time (s) 0.1,Glow (ct2) correction factor (0%)).

The inhibitory effect of the compounds on the PI4 KB activity wasevaluated by the IC50 of the response relative to the high (no virus,column 12) and low (virus+no inhibitor, column 11) controls by fittingto a four parameter dose response equation.

When tested in this assay: all compounds gave a mean pIC50 equal to orgreater than 7.2; compounds 1-8, 10-15 and 17-87 gave a mean pIC50 ofgreater or equal to 7.6; compounds 1, 3, 5, 6, 7, 10-12, 14, 15, 17-25,29, 31, 33-37, 39-53, 55-59, 61-68, 70, 76, 80-82, 84 and 86 gave a meanpIC50 of greater than or equal to 8.4; Compounds 17 and 19 gave a meanpIC50 of 8.9; Compound 21 gave a mean pIC50 of 8.8; and Compound 22 gavea mean pIC50 of at least 9.1.

d) Human Microsomal Metabolic Stability Assay

Protocol Summary

Test compound (0.5 μM) was incubated with pooled liver microsomes. Testcompound was incubated over the course of a 45 min experiment and thetest compound was analysed by LC-MS/MS.

Experimental Procedure

Pooled human liver microsomes were purchased from a reputable commercialsupplier, for example Corning Life Sciences. Microsomes (final proteinconcentration 0.5 mg/mL), 50 mM phosphate buffer pH7.4 and NADPH (finalconcentration=1 mM) were pre-incubated at 37° C. prior to the additionof test compound (final substrate concentration=0.5 μM; final DMSOconcentration=0.25%) to initiate the reaction. The final incubationvolume was 500 μL. A control incubation was included for each compoundtested where 50 mM phosphate buffer pH7.4 was added instead of NADPH(minus NADPH). Two control compounds were included with each species.All incubations are performed singularly for each test compound.

Each compound was incubated for 45 minutes and samples (50 μL) ofincubate were taken at 0, 5, 15, 30 and 45 min. The control (minusNADPH) was sampled at 45 min only. The reactions were stopped by theaddition of 100 μL acetonitrile containing internal standard to thesample. The terminated samples were centrifuged at 2,500 rpm for 20 minat 4° C. to precipitate the protein.

Quantitative Analysis

Following protein precipitation, the samples were analysed using genericLC-MS/MS conditions.

Data Analysis

From a plot of In peak area ratio (compound peak area/internal standardpeak area) against time, the gradient of the line was determined.Subsequently, intrinsic clearance was calculated using the equationsbelow, then converted to mL/min/g:

Elimination rate constant(k)=(−gradient)

Half life(t1/2)(min)=0.693÷k

Intrinsic Clearance(CLint)(μL/min/mg protein)=(V×0.693)÷t _(1/2)

where V=Incubation volume μL/mg microsomal protein.

When tested in this assay, the intrinsic clearance of Compound 17 was28.9 mL/min/g; the intrinsic clearance of Compound 19 was 11.6 mL/min/g;the intrinsic clearance of Compound 21 was 34.0 mL/min/g; and theintrinsic clearance of Compound 22 was 33.7 mL/min/g.

e) Spleen Concentration Assay

Compounds 17, 18, 19, 22 and 23 were tested in this spleen accumulationassay.

Compounds were administered intravenously to rats to determine what thelevel of the compound in the spleen would be if all of the inhaled dosewas absorbed (either orally or through the lungs) and systemiccirculation was exposed to the full dose.

Compounds 17, 19, 22 and 23 were formulated in 2% DMSO in Kleptose (aq,10% w/v). Compound 18 was formulated in a 5:45:50 ratio ofDMSO:PEG200:water. Formulations were administered as intravenousinfusions (1 mg/kg over 1 h) to a single male, Wistar Han rat.

12 hours after the start of dosing, rats were euthanised and spleenswere collected. Approximately 0.5 g samples of spleen were taken andhomogenised in 4 mL water. 100 μL of the resulting homogenates wereprepared by protein precipitation with 300 μL of acetonitrile containingan internal standard and assayed (along with calibration standardsprepared in the same manner) by reversed-phase liquidchromatography—mass spectrometry, using a heated electrospray source andoperated in the positive ion multiple reaction monitoring mode. Theliquid chromatography column used was a Waters Cortecs C18 2.7 μmparticle size, 50×2.1 mm column at 60° C., and the mobile phase,operated as a gradient, utilised (A) 0.1% formic acid (aq) and (B) 0.1%formic acid in acetonitrile, operated at a flow rate of 1 mL/min.

All compounds had a concentration in the spleen of less than 30 ng/g.Compounds 17, 19, 22 and 23 had a concentration in the spleen of lessthan 7 ng/g. In particular, compound 17 had a concentration in thespleen of 1.76 ng/g and compound 22 had a concentration in the spleen of5.54 ng/g.

1. A compound of formula (I) or a pharmaceutically acceptable saltthereof,

wherein W is C, X is C, Y is N and Z is C; W is C, X is N, Y is C and Zis C; W is C, X is N, Y is C and Z is N; W is N, X is C, Y is C and Z isN; or W is N, X is C, Y is C and Z is C; R¹ is C₁₋₄alkoxy,—C(═O)N(R^(1a)R^(1b)), —S(═O)₂—N(R^(1a)R^(1b)), —S(═O)₂—R^(1c) or—S(═O)—R^(1c), wherein R^(1a) is C₁₋₃alkyl, haloC₁₋₃alkyl,hydroxyC₁₋₃alkyl, C₁₋₃alkoxyC₁₋₃alkyl, tetrahydropyranyl ortetrahydrofuranyl; R¹ b is H or C₁₋₃alkyl, or R^(1a) and R^(1b),together with the nitrogen to which they are attached, form a 4- to7-membered ring, which ring contains ring-carbon atoms and optionallyone ring-oxygen atom, wherein the ring is a) optionally substituted byone or two groups selected from C₁₋₃alkyl, halo, C₁₋₃alkoxy, hydroxy,hydroxyC₁₋₃alkyl and oxo, which may be the same or different or b) isortho- or spiro-fused to an unsubstituted 4-6 membered cycloalkane ringor an unsubstituted 4-6 membered saturated heterocyclic ring; and R^(1c)is C₁₋₃alkyl, C₁₋₃alkoxy, hydroxy, hydroxyC₁₋₃alkyl orC₁₋₃alkoxyC₁₋₃alkyl; R² is H, C₁₋₃alkyl, halo or —O—R^(2a), whereinR^(2a) is H or an unsubstituted linear C₁₋₃alkyl chain, wherein onechain carbon is optionally replaced by oxygen; R³ is H or halo; andwherein either i) R^(4a) is H, C₁₋₃alkyl or halo; R^(4b) is C₁₋₃alkyl,cyclopropyl or hydroxyC₁₋₂alkyl; or R^(4a) and R^(4b) together with thecarbon to which they are attached form a 3-6 membered saturated ringcontaining ring-carbon atoms and optionally a ring-oxygen atom, whereinthe ring is optionally substituted by one C₁₋₃alkyl group or onehydroxyC₁₋₂alkyl group; and R^(4c) is OH, hydroxymethyl or hydroxyethyl;ii) R^(4a) H, C₁₋₃alkyl, halo or OH; R^(4b) is H, C₁₋₃alkyl or halo; andR^(4c) is an unsubstituted ring selected from the list consisting ofoxetanyl, tetrahydrofuranyl and tetrahydropyranyl; or iii) R^(4a) is H,and R^(4b) and R^(4c) together with the carbon to which they areattached form an unsubstituted ring selected from the list consisting ofoxetane, tetrahydrofuran or tetrahydropyran; and R⁵ is a) imidazol-2-yloptionally substituted by a C₁₋₃alkyl group at the 1-position andoptionally substituted by a methyl group at the 5-position; or b)pyrazol-1-yl optionally substituted by a C₁₋₃alkyl group at the5-position and optionally substituted by a methyl group at the4-position.
 2. The compound according to claim 1, wherein the compoundis a compound according to formula (Ia) or a pharmaceutically acceptablesalt thereof:

wherein X is N or C, Y is N or C and Z is N or C; wherein X and Y cannotboth be N or both be C; and wherein when Z is N, X is N and Y is C; R¹is C₁₋₄alkoxy, —C(═O)N(R^(1a)R^(1b)), —S(═O)₂—N(R^(1a)R^(1b)),—S(═O)₂—R^(1c) or —S(═O)—R^(1c), wherein R^(1a) is C₁₋₃alkyl,haloC₁₋₃alkyl, hydroxyC₁₋₃alkyl or C₁₋₃alkoxyC₁₋₃alkyl; R^(1b) is H orC₁₋₃alkyl, or R^(1a) and R^(1b), together with the nitrogen to whichthey are attached, form a 4- to 7-membered ring, which ring containsring-carbon atoms and optionally one ring-oxygen atom, wherein the ringis a) optionally substituted by one or two groups selected fromC₁₋₃alkyl, halo, C₁₋₃alkoxy, hydroxy and oxo, which may be the same ordifferent or b) is ortho- or spiro-fused to an unsubstituted 4-6membered cycloalkane ring or an unsubstituted 4-6 membered saturatedheterocyclic ring; and R^(1c) is C₁₋₃alkyl, C₁₋₃alkoxy, hydroxy,hydroxyC₁₋₃alkyl or C₁₋₃alkoxyC₁₋₃alkyl; R² is H, C₁₋₃alkyl, chloro or—O—R^(2a), wherein R^(2a) is H or an unsubstituted linear C₁₋₃alkylchain, wherein one chain carbon is optionally replaced by oxygen; R³ isH or fluoro; R^(4a) is H or methyl; R^(4b) is C₁₋₃alkyl orhydroxyC₁₋₂alkyl; and R⁵ is a) imidazol-2-yl optionally substituted by aC₁₋₃alkyl group at the 1-position and optionally substituted by a methylgroup at the 5-position; or b) pyrazol-1-yl optionally substituted by aC₁₋₃alkyl group at the 5-position and optionally substituted by a methylgroup at the 4-position.
 3. The compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein: i) R^(4a) is H,C₁₋₃alkyl or fluoro; R^(4b) is C₁₋₃alkyl, cyclopropyl orhydroxyC₁₋₂alkyl; or R^(4a) and R^(4b) together with the carbon to whichthey are attached form a 3-6 membered saturated ring containingring-carbon atoms and optionally a ring-oxygen atom, wherein the ring isoptionally substituted by one C₁₋₃alkyl group or one hydroxyC₁₋₂alkylgroup; and R^(4c) is OH, hydroxymethyl or hydroxyethyl; ii) R^(4a) H,C₁₋₃alkyl, fluoro or OH; R^(4b) is H, C₁₋₃alkyl or fluoro; and R^(4c) isan unsubstituted ring selected from the list consisting of oxetanyl,tetrahydrofuranyl and tetrahydropyranyl; or iii) R^(4a) is H, and R^(4b)and R^(4c) together with the carbon to which they are attached form anunsubstituted ring selected from the list consisting of oxetane,tetrahydrofuran or tetrahydropyran.
 4. The compound according to claim 1or a pharmaceutically acceptable salt thereof, wherein R² is H,C₁₋₃alkyl, chloro or —O—R^(2a), wherein R^(2a) is H or an unsubstitutedlinear C₁₋₃alkyl chain, wherein one chain carbon is optionally replacedby oxygen; and R³ is H or fluoro.
 5. (canceled)
 6. (canceled)
 7. Thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein R¹ is —C(═O)N(R^(1a)R^(1b)) or —S(═O)₂—R^(1c).
 8. Thecompound according to claim 7 or a pharmaceutically acceptable saltthereof, wherein R¹ is —C(═O)N(R^(1a)R^(1b)).
 9. The compound accordingto claim 8 or a pharmaceutically acceptable salt thereof, wherein R^(1a)is hydroxyC₁₋₃alkyl or tetrahydropyranyl.
 10. The compound according toclaim 9 or a pharmaceutically acceptable salt thereof, wherein R^(1a) ishydroxyC₁₋₃alkyl.
 11. The compound according to claim 10 or apharmaceutically acceptable salt thereof, wherein R^(1a) is3-hydroxy-1-propyl, 2-hydroxy-1-ethyl or 3-hydroxy-2-propyl.
 12. Thecompound according to claim 8 or a pharmaceutically acceptable saltthereof, wherein R^(1b) is C₁₋₃alkyl.
 13. The compound according toclaim 12 or a pharmaceutically acceptable salt thereof, wherein R^(1b)is methyl or ethyl.
 14. The compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein R² is C₁₋₃alkyl,chloro or —O—R^(2a).
 15. The compound according to claim 14 or apharmaceutically acceptable salt thereof, wherein R² is C₁₋₃alkyl,chloro or methoxy.
 16. The compound according to claim 1 or apharmaceutically acceptable salt thereof, wherein R³ is H.
 17. Thecompound according to claim 1 or a pharmaceutically acceptable saltthereof, wherein R^(4a) is methyl.
 18. The compound according to claim 1or a pharmaceutically acceptable salt thereof, wherein R^(4b) isC₁₋₃alkyl.
 19. The compound according to claim 1 or a pharmaceuticallyacceptable salt thereof, wherein R^(4a) is methyl and R^(4b) is methyl.20. The compound according to claim 1 or a pharmaceutically acceptablesalt thereof, wherein R⁵ is imidazol-2-yl optionally substituted by aC₁₋₃alkyl group at the 1-position and optionally substituted by a methylgroup at the 5-position.
 21. The compound according to claim 20 or apharmaceutically acceptable salt thereof, wherein R⁵ is1-methyl-1H-imidazol-2-yl.
 22. (canceled)
 23. (canceled)
 24. (canceled)25. (canceled)
 26. (canceled)
 27. (canceled)
 28. (canceled) 29.(canceled)
 30. (canceled)
 31. A method of treating a viral infection,comprising administering a compound defined in claim 1 or apharmaceutically acceptable salt thereof, to a patient in need thereof.32. A method of treating a disorder caused or exacerbated by a viralinfection, comprising administering a compound defined in claim 1 or apharmaceutically acceptable salt thereof, to a patient in need thereof.33. A pharmaceutical formulation comprising i) a compound defined inclaim 1 or a pharmaceutically acceptable salt thereof, and ii) apharmaceutically acceptable excipient.
 34. A method of making thecompound of claim 1, wherein R^(4a) and R^(4b) are C₁₋₃alkyl and R^(4c)is OH, as shown in formula (Ix′),

comprising treating a compound of formula (VII) with a oronic ester, inthe presence of a catalyst in a solvent with a base.